AU2006268589B2 - Urea glucokinase activators - Google Patents

Abstract

The invention provides a compound of general formula (I) wherein the substituents are defined futher in the application, as well as further embodiments hereof described in the attached embodiments. The present invention also provides use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes.

Description

UREA GLUCOKINASE ACTIVATORS FIELD OF THE INVENTION This application relates to novel urea glucokinase activators and their use in treatment of assorted diseases. 5 BACKGROUND OF THE INVENTION Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. 10 P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1 48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic p-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types 15 that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 20 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (=10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These 25 findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in p-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while 30 animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in -cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.

- 1a The finding that type i maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in WO 2007/006814 PCT/EP2006/064289 2 humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in hu mans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with 5 an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type 2 diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type 2 diabetes. Glucokinase activators will in 10 crease the flux of glucose metabolism in p-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type || diabetes. Sev eral GK activators are known, see, for example, US 2004/0014968 (Hofmann-La Roche Inc.), WO 2003/055482 (Novo Nordisk A/S) and WO 2004/002481 (Novo Nordisk A/S). Diabetes is characterised by an impaired glucose metabolism manifesting itself among other 15 things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: Type 1 diabetes, or insulin demanding dia betes mellitus (IDDM), which arises when patients lack p-cells producing insulin in their pan creatic glands, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired p-cell function besides a range of other abnormali 20 ties. Type 1 diabetic patients are currently treated with insulin, while the majority of type 2 diabetic patients are treated either with sulphonylureas that stimulate p-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin metformin is a representative ex 25 ample. Even though sulphonylureas are widely used in the treatment of NIDDM this therapy is, in most instances, not satisfactory: In a large number of NIDDM patients sulphonylureas do not suffice to normalise blood sugar levels and the patients are, therefore, at high risk for acquir ing diabetic complications. Also, many patients gradually lose the ability to respond to treat 30 ment with sulphonylureas and are thus gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the p-cells in NIDDM patients. In normal subjects as well as in diabetic subjects, the liver produces glucose in order to avoid hypoglycaemia. This glucose production is derived either from the release of glucose from 35 glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glu- WO 2007/006814 PCT/EP2006/064289 3 cose. In type 2 diabetes, however, the regulation of hepatic glucose output is poorly con trolled and is increased, and may be doubled after an overnight fast. Moreover, in these pa tients there exists a strong correlation between the increased fasting plasma glucose levels and the rate of hepatic glucose production. Similarly, hepatic glucose production will be in 5 creased in type 1 diabetes, if the disease is not properly controlled by insulin treatment. Since existing forms of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfactory, there is a great demand for novel therapeutic approaches. Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclero 10 sis and occlusive heart disease is well known. The earliest stage in this sequence is the for mation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in colour due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Fur ther, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give 15 rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and pro teoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell de bris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fi brous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing 20 to the "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis. Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, 25 and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particular high risk. Independent risk factors include glucose intolerance, left ventricular hy pertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially 30 prevalent among diabetic subjects, at least in part because of the existence of multiple inde pendent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical impor tance. Hypertension (or high blood pressure) is a condition, which occurs in the human population 35 as a secondary symptom to various other disorders such as renal artery stenosis, pheo- WO 2007/006814 PCT/EP2006/064289 4 chromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such "essential" hyper tension is often associated with disorders such as obesity, diabetes, and hypertriglyceride mia, the relationship between these disorders has not been elucidated. Additionally, many 5 patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder. It is known that hypertension can directly lead to heart failure, renal failure, and stroke (brain haemorrhaging). These conditions are capable of causing short-term death in a patient. Hy pertension can also contribute to the development of atherosclerosis and coronary disease. 10 These conditions gradually weaken a patient and can lead to long-term death. The exact cause of essential hypertension is unknown, though a number of factors are be lieved to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin aldosterone system), exces sive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vascu 15 lature resulting in constricted blood vessels and genetic factors. The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus a broad range of beta-blockers, vasoconstrictors, angiotensin converting en zyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention 20 of short-interval deaths such as heart failure, renal failure, and brain haemorrhaging. How ever, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being re duced, the underlying cause of essential hypertension is not responding to this treatment. Hypertension has been associated with elevated blood insulin levels, a condition known as 25 hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to pro mote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of pe 30 ripheral capillaries, while sodium retention increases blood volume. Thus, the lowering of in sulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviates hypertension. Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocar dial infarction, and congestive heart failure. Theses cardiac events are due, at least in part, to 35 increased susceptibility to myocardial injury after ischemia and reperfusion, which can occur WO 2007/006814 PCT/EP2006/064289 5 in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery are 5 considered to be at risk, with incidences of perioperative death and serious cardiac complica tions as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no drug therapy in this area, which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resis 10 tance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospi talizations, enhance quality of life and reduce overall health care costs of high risk patients. Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world. Except for exer 15 cise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exists. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity and/or means of appetite regulation. The term obesity implies an excess of adipose tissue. In this context obesity is best viewed 20 as any degree of excess adiposity that imparts a health risk. The cut off between normal and obese individuals can only be approximated, but the health risk imparted by the obesity is probably a continuum with increasing adiposity. The Framingham study demonstrated that a 20% excess over desirable weight clearly imparted a health risk (Mann GV N.Engl.J.Med 291:226, 1974). In the United States a National Institutes of Health consensus panel on obe 25 sity agreed that a 20% increase in relative weight or a body mass index (BMI = body weight in kilograms divided by the square of the height in meters) above the 85th percentile for young adults constitutes a health risk. By the use of these criteria 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United States are obese. (NIH, Ann Intern Med 103:147,1985). 30 Even mild obesity increases the risk for premature death, diabetes, hypertension, atheroscle rosis, gallbladder disease, and certain types of cancer. In the industrialised western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.

-6 When energy intake exceeds expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity. 5 The regulation of eating behaviour is incompletely understood. To some extent appetite is controlled by discrete areas in the hypothalamus: a feeding centre in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus (VMH). The cerebral cortex receives positive signals from the feeding centre that stimulate eating, and the satiety centre modulates this process by sending 10 inhibitory impulses to the feeding centre. Several regulatory processes may influence these hypothalamic centres. The satiety centre may be activated by the increases in plasma glucose and/or insulin that follow a meal. Meal induced gastric distension is another possible inhibitory factor. Additionally the hypothalamic centres are sensitive to catecholamines, and beta adrenergic stimulation inhibits eating behaviour. Ultimately, 15 the cerebral cortex controls eating behaviour, and impulses from the feeding centre to the cerebral cortex are only one input. Psychological, social, and genetic factors also influence food intake. At present a variety of techniques are available to effect initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem 20 is that most obese patients eventually regain their weight. An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. 25 SUMMARY OF THE INVENTION The invention provides a compound of general formula (1) 0 R INNk N A 12 H R (1) wherein the substituents are defined below, as well as further embodiments hereof described in the attached embodiments.

- 6a The present invention also provides use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes. According to a first aspect, the present invention provides a compound having the 5 formula:

R

3 0 N '0IN H R 30 wherein

R

3 is selected from the group consisting of phenoxy and benzyloxy, each of which is 10 optionally substituted with one or more substituents independently selected from R 2 ;

R

12 is F, Cl, Br, -CF 3 , -CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH 3 , or -S(O) 2

-CH

3 ;

R

3 0 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy, or 15 cyclopropyl-methoxy, each of which is optionally substituted with one or more substituents independently selected from R 1 2; S A is 20 R 8 is methylthio, isopropylthio, ethylthio, or 2-methylpropylthio, each of which is substituted with one or more substituents independently selected from R 3 4 ;

R

34 is carboxy; or a pharmaceutically acceptable salt thereof. According to a second aspect, the present invention provides use of a compound 25 according to the invention for the preparation of a medicament for the treatment of a metabolic disorder, for blood glucose lowering, for the treatment of hyperglycemia, for the treatment of IGT, for the treatment of Syndrome X, for the treatment of impaired fasting glucose (IFG), for the treatment of type-2 diabetes, for the treatment of type-1 - 6b diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type-2 diabetes, for delaying the progression of non-insulin requiring type-2 diabetes to insulin requiring type-2 diabetes, for the treatment of dyslipidemia, for the treatment of hyper lipidemia, for the treatment of hypertension, for lowering of food intake, for appetite 5 regulation, for the treatment of obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. According to a third aspect, the present invention provides a method for treating a metabolic disorder, for lowering blood glucose levels, treating hyperglycemia, treating IGT, treating Syndrome X, treating impaired fasting glucose (IFG), treating type-2 10 diabetes, treating type-1 diabetes, delaying the progression of impaired glucose tolerance (IGT) to type-2 diabetes, delaying the progression of non-insulin requiring type-2 diabetes to insuling requiring type-2 diabetes, treating dyslipidemia, treating hyperlipidemia, treating hypertension, lowering of food intake, appetite regulation, treating obesity, regulating feeding behaviour, or enhancing the secretion of 15 enteroincretins said method comprising the step of administering to a subject in need thereof a compound according to the invention. According to a fourth aspect, the present invention provides a method of treating an indication selected from the group consisting of hyperglycemia, IGT, insulin resistance syndrome, syndrome X, type-2 diabetes, type-1 diabetes, dyslipidemia, hypertension, 20 and obesity said method comprising the step of administering to a subject in need thereof a compound according to the invention. Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the 25 sense of "including, but not limited to".

DEFINITIONS

WO 2007/006814 PCT/EP2006/064289 7 In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning: The term "optionally substituted" as used herein means that the moiety which is optionally substituted is either unsubstituted or substituted with one or more of the substituents speci 5 fied. When the moiety in question is substituted with more than one substituent, the substitu ent may be the same or different. The term "adjacent" as used herein regards the relative positions of two atoms or variables, these two atoms or variables sharing a bond or one variable preceding or succeeding the other in a variable specification. By way of example, "atom A adjacent to atom B" means that 10 the two atoms A and B share a bond. The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine. The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl, or triio domethyl. The use of prefixes of this structure: Cx-y-alkyl, Cx-y-alkenyl, Cx-y-alkynyl, Cx-y-cycloalyl or Cx-y 15 cycloalkyl-Cx-y-alkenyl- and the like designates radical of the designated type having from x to y carbon atoms. The term "alkyl" as used herein, alone or in combination, refers to a straight or branched chain saturated monovalent hydrocarbon radical having from one to ten carbon atoms, for example C1.

8 -alkyl or C1.

6 -alkyl. Typical C1.

8 -alkyl groups and C1.

6 -alkyl groups include, but 20 are not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2 dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C_ 8 -alkyl" as used herein also includes secondary C 3

-

8 -alkyl and tertiary C4_ 8 -alkyl. The term "C_ 6 -alkyl" as used herein also includes secondary C 3

-

6 -alkyl and tertiary C4_ 6 -alkyl. 25 The term " alkenyl" as used herein, alone or in combination, refers to a straight or branched chain monovalent hydrocarbon radical containing from two to ten carbon atoms and at least one carbon-carbon double bond, for example C2.

8 -alkenyl or C2.

6 -alkenyl. Typical C2.

8 -alkenyl groups and C 2

-

6 -alkenyl groups include, but are not limited to, vinyl, 1 -propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1 -butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 -propenyl, 1 30 pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3 hexenyl, 2,4-hexadienyl, 5-hexenyl and the like. The term "alkynyl" as used herein alone or in combination, refers to a straight or branched monovalent hydrocarbon radical containing from two to ten carbon atoms and at least one triple carbon-carbon bond, for example C2.

8 -alkynyl or C2.

6 -alkynyl. Typical C2.

8 -alkynyl 35 groups and C 2

-

6 -alkynyl groups include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, WO 2007/006814 PCT/EP2006/064289 8 1 -butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -hexynyl, 2 hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like. The term "cycloalkyl" as used herein, alone or in combination, refers to a saturated mono-, bi-, or tricarbocyclic radical having from three to twelve carbon atoms, for example C3-8 5 cycloalkyl. Typical C 3

-

8 -cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobu tyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.2.1 ]octyl, bicyclo[2.2.1 ]heptyl, norpinyl, norbonyl, norcaryl, adamantyl and the like. The term "cycloalkenyl" as used herein, alone or in combination, refers to an non-aromatic unsaturated mono-, bi-, or tricarbocyclic radical having from three to twelve carbon atoms, for 10 example C 3

-

8 -cycloalkenyl. Typical C 3

-

8 -cycloalkyl groups include, but are not limited to cyclo hexene, cycloheptene and cyclopentene, and the like. The term "heterocyclic" or the term "heterocyclyl" as used herein, alone or in combination, refers to a saturated mono-, bi-, or tricarbocyclic group having three to twelve carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, 15 SO or SO 2 , for example C 3

-

8 -heterocyclyl. Typical C 3

-

8 -heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, and the like. The term "heterocycloalkenyl" as used herein, alone or in combination, refers to a non aromatic unsaturated mono-, bi-, or tricyclic radical having from three to twelve carbon at 20 oms, and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sul phur, SO or SO 2 , for example C 3

-

8 -hetereocycloalkenyl. Typical C 3

-

8 -hetreocycloalkenyl groups include, but are not limited to tetrahydropyridine, azacycloheptene, 2-pyrroline, 3 pyrroline, 2-pyrazoline, imidazoline, 4H-pyran, and the like. The terms "alkoxy" or "alkyloxy", which are interchangeable terms herein, as used herein, 25 alone or in combination, refers to the monovalent radical RaO-, where R' is alkyl as defined above, for example C1.

8 -alkyl giving C 1

.

8 -alkoxy. Typical C1.

8 -alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pen toxy, isopentoxy, hexoxy, isohexoxy and the like. The term "alkenyloxy", as used herein, alone or in combination, refers to the monovalent 30 radical RaO-, where R' is alkenyl as defined above, for example C 2

-

8 -alkyl giving C28 alkenyloxy. Typical C 2

-

8 -alkenyloxy groups include, but are not limited to, vinyloxy, propeny loxy, 2-methyl-propenyloxy, butenyloxy, and the like. The term "alkenylthio", as used herein, alone or in combination, refers to the monovalent radical R'S-, where R' is alkenyl as defined above, for example C 2

-

8 -alkyl giving C2-8- WO 2007/006814 PCT/EP2006/064289 9 alkenylthio. Typical C 2

-

8 -alkenyloxy groups include, but are not limited to, vinylthio, propenyl thio, 2-methyl-propenylthio, and the like. The term "alkylthio" as used herein, alone or in combination, refers to a straight or branched monovalent radical comprising an alkyl group as described above linked through a divalent 5 sulphur atom having its free valence bond from the sulphur atom, for example C_ 6 -alkylthio. Typical C_ 6 -alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like. The term "alkoxycarbonyl" as used herein refers to the monovalent radical RaOC(O)-, where R' is alkyl as described above, for example C_ 8 -alkoxycarbonyl. Typical C_ 8 -alkoxycarbonyl 10 groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tertbutoxycarbonyl, 3 methylbutoxycarbonyl, n-hexoxycarbonyl and the like. The term "aryl" as used herein refers to a carbocyclic aromatic ring radical or to an aromatic ring system radical. Aryl is also intended to include the partially hydrogenated derivatives of 15 the carbocyclic systems. The term "heteroaryl", as used herein, alone or in combination, refers to an aromatic ring radical with for instance 5 to 7 member atoms, or to a aromatic ring system radical with for instance from 7 to 18 member atoms, containing one or more heteroatoms selected from ni trogen, oxygen, or sulphur heteroatoms, wherein N-oxides and sulphur monoxides and sul 20 phur dioxides are permissible heteroaromatic substitutions; such as e.g. furanyl, thienyl, thio phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl, and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems 25 enumerated below. Examples of "aryl" and "heteroaryl" includes, but are not limited to phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3 anthracenyl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin, fluorenyl, xanthenyl, isoindanyl, 30 benzhydryl, acridinyl, thiazolyl, pyrrolyl (1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1 pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4 imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1 -yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl, 1,2,4 triazol-3-yl, 1,2,4-triazol-5-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4-yl, isooxaz-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl, 35 isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4- WO 2007/006814 PCT/EP2006/064289 10 pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyri dazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4 isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2 5 benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3 dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6 (2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, 10 benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), 2,3-dihydro-benzo[b]thiophenyl (2,3-dihydro benzo[b]thiophen-2-yl, 2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl, 2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl, 2,3-dihydro benzo[b]thiophen-7-yl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7 indolyl), indazole (1 -indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), 15 benzimidazolyl (1 -benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6 benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxazolyl, 3 benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 7-benzoxazolyl), benzothia zolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7 benzothiazolyl), carbazolyl (1 -carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H 20 dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1 -yl, 5H-dibenz[b,f]azepine-2-yl, 5H dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11 dihydro-5H-dibenz[b,f]azepine (10,11 -dihydro-5H-dibenz[b,f]azepine-1 -yl, 10,11 -dihydro-5H dibenz[b,f]azepine-2-yl, 10,11 -dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11 -dihydro-5H dibenz[b,f]azepine-4-yl, 10,11 -dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole (2 25 benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole, 6-benzo[1,3]dioxole, 7 benzo[1,3]dioxole), purinyl, and tetrazolyl (5-tetrazolyl, N-tetrazolyl). The present invention also relates to partly or fully saturated analogues of the ring systems mentioned above. When two or more of the above defined terms are used in combination, such as in aryl-alkyl, 30 heteroaryl-alkyl, cycloalkyl-C_ 6 -alkyl and the like, it is to be understood that the first men tioned radical is a substituent on the latter mentioned radical, where the point of substitution, i.e. the point of attachment to another part of the molecule, is on the latter of the radicals, for example WO 2007/006814 PCT/EP2006/064289 11 aryl-alkyl-: cycloalkyl-alkyl-: , and aryl-alkoxy-: The term "fused arylcycloalkyl", as used herein, refers to an aryl group, as defined above, 5 fused to a cycloalkyl group, as defined above and having the indicated number of carbon at oms, the aryl and cycloalkyl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of "fused arylcycloalkyl" used herein include 1 indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl), and the like. 10 The term "fused heteroarylcycloalkyl", as used herein, refers to a heteroaryl group, as de fined above, fused to a cycloalkyl group, as defined above and having the indicated number of carbon atoms, the aryl and cycloalkyl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of fused heteroarylcycloalkyl used 15 herein include 6,7-dihydro-5H-cyclopenta[b]pyridine, 5,6,7,8-tetrahydroquinoline, 5,6,7,8 tetrahydrisoquinoline, 5,6,7,8-tetrahydroquinazoline and the like The term "alkylsulfanyl", as used herein, refers to the group R'S-, where R' is alkyl as de scribed above. The term "alkylsulfenyl", as used herein, refers to the group RaS(O)-, where R' is alkyl as de 20 scribed above. The term "alkylsulfonyl", as used herein, refers to the group R"SO 2 -, where R" is alkyl as de scribed above. The term "alkylsulfamoyl", as used herein, refers to the group RaNHSO 2 -, where R' is alkyl as described above.

WO 2007/006814 PCT/EP2006/064289 12 The term "dialkylsulfamoyl", as used herein, refers to the group RaRbNSO 2 -, where R' and Rb are alkyl as described above. The term "alkylsulfinamoyl", as used herein, refers to the group RaNHSO-, where R' is alkyl as described above. 5 The term "dialkylsulfinamoyl", as used herein, refers to the group RaRbNSO-, where R' and Rb are alkyl as described above. The term "alkylamino", as used herein, refers to the group RNH-, where R' is alkyl as de scribed above. The term "acyl", as used herein, refers to the group RaC(O)-, where R' is alkyl, alkenyl, al 10 kynyl, cycloalkyl, cycloalkenyl, or heterocyclyl as described above. The term "heteroaryloxy" as used herein, alone or in combination, refers to the monovalent radical R"O-, where R' is heteroaryl as defined above. The term "aryloxycarbonyl", as used herein, refers to the group Ra-O-C(O)-, where R' is aryl as described above. 15 The term "acyloxy", as used herein, refers to the group RaC(O)O-, where R' is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl as described above. The term "aryloxy", as used herein refers to the group Ra-O-, where R' is aryl as described above. The term "aroyloxy", as used herein, refers to the group RaC(O)O-, where R' is aryl as de 20 scribed above. The term "heteroaroyloxy", as used herein, refers to the group RaC(O)O-, where R' is het eroaryl as described above. Whenever the terms "alkyl", "cycloalkyl", "aryl", "heteroaryl" or the like or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as 25 including those limitations given above for "alkyl" and "aryl". As used herein, the term "oxo" shall refer to the substituent =0. As used herein, the term "mercapto" shall refer to the substituent -SH. As used herein, the term "carboxy" shall refer to the substituent -C(O)OH. As used herein, the term "cyano" shall refer to the substituent -CN. 30 As used herein, the term "nitro" shall refer to the substituent -NO 2 . As used herein, the term "aminosulfonyl" shall refer to the substituent -SO 2

NH

2 . As used herein, the term "sulfanyl" shall refer to the substituent -S-. As used herein, the term "sulfenyl" shall refer to the substituent -S(O)-. As used herein, the term "sulfonyl" shall refer to the substituent -S(0) 2

-.

WO 2007/006814 PCT/EP2006/064289 13 As used herein, the term "direct bond", where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond". The term "lower", as used herein, refers to an group having between one and six carbons, 5 and may be indicated with the prefix Cx-. Lower alkyl may thus be indicated as C1.

6 -alkyl, while lower alkylene may be indicated as C 2 6 -alkylene. A radical such as Cxy-cycloalkyl-Cabe-alkenyl shall designate that the radical's point of at tachment is in part of the radical mentioned last. As used herein, the term "optionally" means that the subsequently described event(s) may or 10 may not occur, and includes both event(s) which occur and events that do not occur. As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. As used herein, the term "attached" or "-" (e.g. -C(O)R 11 which indicates the carbonyl at tachment point to the scaffold) signifies a stable covalent bond. 15 As used herein, the terms "contain" or "containing" can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of 0, S, SO, SO 2 , N, or N-alkyl, including, for example, -CH 2 -0-CH 2 -, -CH 2

-SO

2 CH 2 -, -CH 2

-NH-CH

3 and so forth. Certain of the above defined terms may occur more than once in the structural formulae, and 20 upon such occurrence each term shall be defined independently of the other. As used herein, the term "solvate" is a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (1)) and a solvent. Such solvents for the purpose of the present invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid. 25 As used herein, the term "biohydrolyzable ester" is an ester of a drug substance (in this in vention, a compound of formula (1) ) which either a) does not interfere with the biological ac tivity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is 30 that, for example, the biohydrolyzable ester is orally absorbed from the gut and is trans formed to (1) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters (e.g., C14), lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. As used herein, the term "biohydrolyzable amide" is an amide of a drug substance (in this 35 invention, a compound of general formula (1)) which either a) does not interfere with the bio- WO 2007/006814 PCT/EP2006/064289 14 logical activity of the parent substance but confers on that substance advantageous proper ties in vivo such as duration of action, onset of action, and the like, or b) is biologically inac tive but is readily converted in vivo by the subject to the biologically active principle. The ad vantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is 5 transformed to (1) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoal kylcarbonyl amides. As used herein, the term "prodrug" includes biohydrolyzable amides and biohydrolyzable es ters and also encompasses a) compounds in which the biohydrolyzable functionality in such 10 a prodrug is encompassed in the compound of formula (1) and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of for mula (1). Examples of these functional groups include, but are not limited to, 1,4 dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like. 15 The term "pharmacologically effective amount" or shall mean that amount of a drug or phar maceutical agent that will elicit the biological or medical response of a tissue, animal or hu man that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount. The term therapeuticallyy effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human 20 that is being sought. The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the full spectrum of treatments for a given disorder from which the patient is suffering, such as the delaying of the progression of the disease, disorder or condition, the alleviation 25 or relief of symptoms and complications, the prevention of the disease and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being. The term "pharmaceutically acceptable salt" as used herein includes pharmaceutically ac ceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceuti 30 cally acceptable metal salts, ammonium salts, and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and nitric acids. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, 35 maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, WO 2007/006814 PCT/EP2006/064289 15 ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesul fonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, ace tates, benzoates, hydroxynaphthoates, glycerophosphates, and ketoglutarates. Further ex 5 amples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magne sium, zinc, and calcium salts. Examples of amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu 10 tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N methyl-D-glucamine, and guanidine. Examples of cationic amino acids include lysine, argin ine, and histidine. The pharmaceutically acceptable salts are prepared by reacting the compound of formula I 15 with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hy dride, potassium t-butoxide, calcium hydroxide, and magnesium hydroxide, in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever appli 20 cable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, ni tric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, and tartaric acid in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used. 25 The term "combination therapy", "combined", "in combination with", and the like, as used herein refers to the administration of a single pharmaceutical dosage formulation which com prises the glucokinase activator compound of the present invention and another active agent(s), as well as administration of each active agent(s) in its own separate pharmaceutical dosage formulation. Where separate dosage formulations are used, the compound of the 30 present invention and another active agent(s) can be administered to the patient at essen tially the same time, i.e. concurrently, or at separate staggered times, i.e. sequentially. When given by different dosage formulations, the route of administration may be the same or differ ent for each agent. Any route of administration known or contemplated for the individual agents is acceptable for the practice of the present invention. 35 WO 2007/006814 PCT/EP2006/064289 16 DESCRIPTION OF THE INVENTION In an embodiment 1 the invention provides a compound of general formula (1) 0 R A N N 12 H 5 R wherein R 1 is C1_ 8 -alkyl, C 2

-

8 -alkenyl, C 2

-

8 -alkynyl, aryl, heteroaryl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl,

C

38 -cycloalkyl-C2.

6 -alkenyl, C 3

-

8 -cycloalkyl-C2.

6 -alkynyl, C 3

-

8 -cycloalkenyl-C_ 6 -alkyl, C3.8 cycloalkenyl-C 2

-

6 -alkenyl, C 3

-

8 -cycloalkenyl-C 2

-

6 -alkynyl, C 3

-

8 -heterocyclyl-C_ 6 -alkyl, C38 heterocyclyl-C 2

-

6 -alkenyl, C 3

-

8 -heterocyclyl-C 2

-

6 -alkynyl, C 3

-

8 -heterocycloalkenyl-C_ 6 -alkyl, C3. 10 8 -heterocycloalkenyl-C 2

-

6 -alkenyl, C 3

-

8 -heterocycloalkenyl-C 2

-

6 -alkynyl, aryl-C_ 6 -alkyl, aryl-C2_ 6 -alkenyl, aryl-02- 6 -alkynyl, heteroaryl-C_ 6 -alkyl, heteroaryl-C 2

-

6 -alkenyl, heteroaryl-C 2 6 alkynyl, (fused aryl-C 3

-

8 -cycloalkyl)-C 1

.

6 -alkyl, (fused aryl-C 3 -- cycloalkyl)-C 2 -- alkenyl, (fused aryl-C 3 -- cycloalkyl)-C 2 -- alkynyl, (fused heteroaryl-C 3

-

8 -cycloalkyl)-C_ 6 -alkyl, (fused het eroaryl-C 3

-

8 -cycloalkyl)-C 2

-

6 -alkenyl or (fused heteroaryl-C 3

-

8 -cycloalkyl-C 2

-

6 -alkynyl) each of 15 which is optionally substituted with one or more substituents R 3 , R 4 , R 5 and R 6 ;

R

2 is C1_ 8 -alkyl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C_ 8 -alkyl, C 3

-

8 -cycloalkenyl, C 3

-

8 -heterocyclyl,

C

3 -- heterocycloalkenyl, fused aryl-C 3

-

8 -cycloalkyl, or fused heteroaryl-C 3

-

8 -cycloalkyl, each of which is optionally substituted with one or more substituents R 3 0 , R 31 , R 3 2 and R 3 3 ; 20

R

3 , R 4 , R 5 , R 6 , R 30 , R 31 , R 32 and R 33 are independently selected from the group consisting of * halogen, nitro, cyano, hydroxy, oxo, carboxy, -CF 3 ; or * -NR 10 R; or *Cl_ 6 -alkyl, C 2

-

6 -alkenyl, C 2

-

6 -alkynyl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C3-8 25 cycloalkyl-C 3

-

6 -alkenyl, aryl, aryl-C 1

.

6 -alkyl, aryl-C 2

-

6 -alkenyl, heteroaryl-C_ 6 -alkyl, het eroaryl-C 2

-

6 -alkenyl, heterocyclyl-C_ 6 -alkyl, heterocyclyl-C 2

-

6 -alkenyl, Cl_ 6 -alkoxy, C3-6 alkenyloxy, C 3

-

8 -cycloalkoxy, C 3

-

6 -cycloalkyl-C 1

.

6 -alkoxy, C 3

-

8 -cycloalkenyl-C 1

.

6 -alkoxy,

C

3

-

8 -heterocyclyl-C_-alkoxy, fused aryl-C 3

-

8 -cycloalkenyl-C_ 6 -alkoxy, C 3

-

8 -cycloalkyl

C

3

-

6 -alkenyloxy, C 3

-

8 -cycloalkenyl-C 3

-

6 -alkenyloxy, C 3

-

8 -heterocyclyl-C 3

-

6 -alkenyloxy, 30 fused C 3

-

8 -cycloalkyl-aryloxy, fused heterocyclyl-aryloxy, fused aryl-C 3

-

8 -cycloalkenyl

C

3

-

6 -alkenyloxy, aryl-C_ 6 -alkoxy, aryl-C 3

-

6 -alkenyloxy, heteroaryl, heteroaryl-C-6 alkoxy, heteroaryl-C 3

-

6 -alkenyloxy, aryloxy, heteroaryloxy, Cl_ 6 -alkylthio, C3-6 alkenylthio, C 3

-

6 -cycloalkyl-Cl_ 6 -alkylthio, C 3

-

8 -cycloalkenyl-Cl_ 6 -alkylthio, C3-8- WO 2007/006814 PCT/EP2006/064289 17 heterocyclyl-Cl_-alkylthio, fused aryl-C 3

-

8 -cycloalkenyl-Cl_ 6 -alkylthio, C 3

-

8 -cycloalkyl

C

3

-

6 -alkenylthio, C 3

-

8 -cycloalkenyl-C 3

-

6 -alkenylthio, C 3

-

8 -heterocyclyl-C 3

-

6 -alkenylthio, fused aryl-C 3

-

8 -cycloalkenyl-C 3

-

6 -alkenylthio, aryl-Cl_ 6 -alkylthio, aryl-C 3

-

6 -alkenylthio, heteroaryl-Cl_ 6 -alkthio, heteroaryl-C 3

-

6 -alkenylthio, arylthio, heteroarylthio amino-C-6 5 alkyl, Cl_ 6 -alkylamino-Cl_ 6 -alkyl, di-(Cl_ 6 -alkyl)amino-Cl_ 6 -alkyl, Cl_ 6 -alkylsulfamoyl, di(C 1

.

6 -alkyl)sulfamoyl, C 1

.

6 -alkylsulfinamoyl or di(C 1

.

6 -alkyl)sulfinamoyl each of which is optionally substituted with one or more substituents independently selected from R1; or * -C(O)-R 27 , -S(O) 2

-R

27 , -C(O)-NR 13

R

1 4 , -S(O) 2

-NR

1 3

R

1 4 , -C 1

_

6 -alkyl-C(O)-NR 1 3

R

14 ; or 10 *two substituents selected from R 3 , R 4 , R and R 6 or R 30 , R 31 , R 3 2 and R 33 attached to the same or adjacent atoms together may form a radical -O-(CH 2

)

13 _-O-;

R

1 0 and R" independently represent hydrogen, Cl_ 6 -alkyl, -C(O)-Cl_ 6 -alkyl, -C(O)-O-Cl_ 6 -alkyl,

-C(O)-C

38 _-cycloalkyl, carboxy-C 1

.

6 -alkyl, -C(O)-C1.

6 -alkyl-C(O)OH, -S(O) 2

-C

1

_

6 -alkyl, or aryl , 15 each of which is optionally substituted with one or more halogens;

R

27 is Cl_ 6 -alkyl, Cl_ 6 -alkoxy, C 2

-

6 -alkenyl, C 2

-

6 -alkynyl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-Cl_ 6 alkyl, C 3

-

8 -cycloalkyl-C 2

-

6 -alkenyl, aryl, aryl-C 1

.

6 -alkyl, aryloxy-C 1

.

6 -alkyl, aryl-C 2

-

6 -alkenyl, het eroaryl, C 3

-

8 -heterocyclyl, heteroaryl-Cl_ 6 -alkyl, C 3

-

8 -heterocyclyl-Cl_ 6 -alkyl, heteroaryloxy-C-6 20 alkyl, carboxy-C 1

.

6 -alkyl, carboxy-C 2

-

6 -alkenyl, C1.

6 -alkoxy-C 1

.

6 -alkyl, C1.

6 -alkoxy-C 2

.

6 -alkenyl, Cl_ 6 -alkylthio-Cl_ 6 -alkyl, R 10

HN-C

1

_

6 -alkyl, ROR 1 -N-Cl_ 6 -alkyl, R 1 0

R

11

-N-C

2

_

6 -alkenyl, R 10

R"-N

S(O)

2

-C

1

.

6 -alkyl, R 1 0

R

11

-N-C(O)-C

1

_

6 -alkyl, C 1

,

6 -alkyl-C(O)-NH-C 1

-

6 -alkyl, aryl-C(O)-NH-Cl_ 6 alkyl, heteroaryl-C(O)-NH-Cl_ 6 -alkyl, C 3

-

8 -cycloalkyl-C(O)-NH-Cl_ 6 -alkyl, C 1

_

6 -alkyl-S(O) 2

-NH

Cl.

6 -alkyl, aryl-S(O) 2

-NH-C

1

_

6 -alkyl, heteroaryl-S(O) 2

-NH-C

1

_

6 -alkyl, or C 3

-

8 -cycloalkyl-S(O) 2 25 NH-C 1

.

6 -alkyl, each of which is optionally substituted with one or more substituents inde pendently selected from R 1 2 ;

R

1 2 is halogen, cyano, hydroxy, -C(O)-O-C 1

-

6 -alkyl, carboxy, -CF 3 , Cl_ 6 -alkyl, aryl, heteroaryl, Cl_-alkoxy, C 2

.

6 -alkenyloxy, C 3

-

8 -cycloalkyloxy, C 3

-

8 -cycloalkenyloxy, C 3

-

8 -heterocyclyloxy, 30 aryloxy, heteroaryloxy, aryl-Cl_ 6 -alkoxy, aryl-Cl_ 6 -alkenyloxy, heteroaryl-Cl_ 6 -alkoxy, het eroaryl-C 1

.

6 -alkenyloxy, C 3

-

8 -cycloalkyl-C 1

.

6 -alkoxy, C 3

-

8 -cycloalkyl-C 1

.

6 -alkenyloxy, C3.8 heterocyclyl-Cl_ 6 -alkoxy, C 3

-

8 -heterocyclyl-Cl_ 6 -alkenyloxy, fused aryl-C 3

-

8 -cycloalkyl-C-6 alkoxy, fused aryl-C 3

-

8 -cycloalkyl-C 1

-

6 -alkenyloxy, C 1

-

6 -alkylthio, C 2

-

6 -alkenylthio, C 3

.

8 cycloalkylthio, C 3

-

8 -cycloalkenylthio, C 3

-

8 -heterocyclylthio, arylthio, heteroarylthio, aryl-C-6 35 alkylthio, aryl-Cl_ 6 -alkenylyhio, heteroaryl-Cl_ 6 -alkyltio, heteroaryl-Cl_ 6 -alkenylthio, C3- WO 2007/006814 PCT/EP2006/064289 18 cycloalkyl-C 1

.

6 -alkylthio, C 3

-

8 -cycloalkyl-C_ 6 -alkenylthio, C 3

-

8 -heterocyclyl-C_ 6 -alkylthio, C3-8 heterocyclyl-C_ 6 -alkenylthio, fused aryl-C 3

-

8 -cycloalkyl-C_ 6 -alkylthio, fused aryl-C 38 cycloalkyl-C 1

.

6 -alkenylthio, -NR 10 R, -S(O) 2

CH

3 , -S(O) 2

CF

3 or -S(O) 2

NH

2 each of which is optionally substituted with one or more substituents independently selected from R 38 ; 5

R

1 3 and R 1 4 are independently selected from the group consisting of hydrogen, C_ 6 -alkyl, hy droxy-C 1

.

6 -alkyl, carboxy-C 1

.

6 -alkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from R 1 5 ; or R 1 3 and R 14 together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the 10 said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur;

R

1 5 is halogen, cyano, hydroxy, carboxy, -CF 3 , C_ 6 -alkyl, -S(O) 2

CH

3 , or -S(O) 2

NH

2 ; 15 R 3 8 is halogen or C_ 6 -alkyl; A is heteroaryl which is substituted with at least one substituent independently selected from R , R 8 and R 9 ; wherein 20 R , R 8 and R 9 are independently selected from e C_ 6 -alkyl, C_ 6 -alkoxy, C_ 6 -alkylthio, C 3

-

6 -cycloalkylthio, C_ 6 -alkylamino, C_ 6 -alkylsu fenyl, -C1- 6 -alkyl-O-C(O)-C 1

.

6 -alkyl, -NH-C(O)-C_ 6 -alkyl, -C_-alkoxy-C_ 6 -alkyl, -C_ 6 -alkyl-S-C_ 6 -alkyl or hydroxy-C_ 6 -alkyl, each of which is substituted with one or more substituents independently selected from R 34 ; or 25 e -C 1

.

6 -alkyl-NR 1 9

R

2 0 , -C2.

6 -alkenyl-NR 1 9

R

20 , -C_ 6 -alkyl-S-R 21 , -C_ 6 -alkyl-S(O)

R

21 , -C1_ 6 -alkyl-S(O) 2

-R

21 , -S(O) 2

-R

21 , -S(O) 2

-N(R

1 9)(C_ 6 -alkyl)-C(O)-NR 22

R

23 or

-S(O)

2

-NR

1 9

R

2 0 , each of which is substituted with one or more substituents inde pendently selected from R 25 ; or * -C(O)NR 2 2

R

23 , -C 1

_

6 -alkyl-C(O)NR 22

R

2 3 each of which is substituted with 30 one or more substituents independently selected from R 25 ; or two of R 7 , R 8 and R 9 can be taken together to form a C 2

-

5 -alkylene bridge; the C 2

-

5 -alkylene bridge is optionally substituted with one or more substituents independently selected from

R

1 6 ; or e carboxy, nitro, hydroxy, -SCN; or WO 2007/006814 PCT/EP2006/064289 19

SC

2

-

6 -alkenyl, C 2

-

6 -alkynyl, Cl_-alkenyoxy, C 2

-

6 -alkenylthio, C 3

-

6 -cycloalkyl,

C

3

-

6 -cycloalkyl-C 1

.

6 -alkyl, C 3

-

6 -cycloalkoxy, C 3

-

6 -cycloalkyl-C_ 6 -alkylthio, -C(O)-O-C1.

6 -alkyl, formyl, -C(O)-C1.

6 -alkyl, -C1.

6 -alkyl-C(O)-O-C 1

.

6 -alkyl, carboxy C1.

6 -alkyl each of which is optionally substituted with one or more substituents in 5 dependently selected from R 16 ; or e heteroaryl, heteroaryl-C_ 6 -alkyl, heteroaryl-C_ 6 -alkoxy, heteroaryl-C-6 alkylthio, heteroaryl-thio-C_ 6 -alkyl, heteroaryl-oxy-C_ 6 -alkyl, heteroaryloxy, het eroarylthio, -C(O)-aryl, or -C(O)-heteroraryl, each of which is optionally substi tuted on the aryl or heteroaryl part with one or more substituents independently 10 selected from R 17 ; or e C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkenyl, C 3

-

8 -cycloalkylthio, C 3

-

8 -cycloalkyl-C_ 6 alkyl, C 3

-

8 -cycloalkenyl-C 1

.

6 -alkyl, C 3

-

6 -cycloalkyl-C 1

.

6 -alkoxy, C 3

-

6 -cycloalkyl-C 1

.

6 alkylthio, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from R 1 8 ; or 15 e C 3

-

8 -heterocyclyl, C 3

-

8 -heterocyclyl-C_ 6 -alkyl, C 3

-

8 -heterocyclyl-C_ 6 -alkylthio,

C

3

-

8 -heterocyclylthio, C 3

-

8 -heterocyclyl-amino-C_ 6 -alkyl, or -C(O)-C38 heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from R 16 ; or * -Cl_-alkyl-NR 3 6

R

3 7 , -C2_ 6 -alkenyl-NR 36

R

37 or -S(O) 2

-NR

36

R

37 , each optionally 20 substituted with one or more substituents independently selected from R 25 ; or C(O)NR 36

R

37 , -C 1

_

6 -alkyl-C(O)NR 36

R

37 , -C 1

_

6 -alkyl-NH-NR 22

R

23 , -Cl_ 6 -alkyl-NH-C(O)-Cl_ 6 -alkyl-NR 22

R

2 3 , each optionally substituted with one or more substituents independently selected from R 26 ; 25 If more than one substituent R 7 , R 8 and R 9 is present on A that additional R 7 , R 8 and R 9 may be selected from halogen or C 1

,

6 -alkyl;

R

16 , R 17 , and R 18 are independently C_ 6 -alkyl, halogen, nitro, cyano, hydroxy, carboxy, oxo,

-CF

3 , carboxy-C 1

.

6 -alkyl, hydroxy-C_ 6 -alkyl, -C1_ 6 -alkyl-C(O)-O-C_ 6 -alkyl, 30 -C1.

6 -aky-C(O)-NR 1 9

R

20 , -C(O)-O-C 1 _-alkyl, -C(O)-C 1

_

6 -alkyl-C(O)-C 1

_

6 -alkyl, -NR 1 9

R

20 ,

-NHS(O)

2 C1_ 6 -alkyl, -NHS(O) 2

CF

3 , -C(O)NR 1 9

R

20 , -S(O) 2 C1_ 6 -alkyl, -S(O) 2

CF

3 , -S(O) 2

CH

2

CF

3 or -S(O) 2

NR

1 9

R

2 0 ;

R

34 is halogen, nitro, cyano, hydroxy, carboxy, -CF 3 ; or WO 2007/006814 PCT/EP2006/064289 20 carboxy-C 1

.

6 -alkyl, -C1.

6 -alkyl-C(O)-O-C 1

.

6 -alkyl, -C(O)-O-C1.

6 -alkyl or -C(O)-C1.

6 -alkyl-C(O)

C

1

,

6 -alkyl each optionally substituted with one or more halogens;

R

1 9 and R 20 independently represent hydrogen, C_ 6 -alkyl, C 2

-

6 -alkenyl, hydroxy-C_ 6 -alkyl, 5 carboxy-C 1

.

6 -alkyl, aryl, heteroaryl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C 3

-

8 -heterocyclyl, aryl-C 1

.

6 -alkyl, C 3

-

8 -heterocyclyl-C_ 6 -alkyl, -C(O)-O-Cl_ 6 -alkyl, -C1_ 6 -alkyl-C(O)-O-C_ 6 -alkyl,

-C

1

.

6 -alkyl-NR 2 2

R

2 3 , or -S(O) 2

-C

1

_

6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 24 , or R 19 and R 2 0 together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen 10 atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 ;

R

21 is selected from 15 e C_ 6 -alkyl, C 2

-

6 -alkenyl , carboxy-C 1

.

6 -alkyl, C_ 6 -alkylamino-C_ 6 -alkyl or hy droxy-C 1

.

6 -alkyl, -C1.

6 -alkyl-NR 22

R

23 ; or e aryl, heteroaryl, aryl-C_ 6 -alkyl, or heteroaryl-C_ 6 -alkyl, wherein the aryl or heteroaryl part is optionally substituted with one or more substituents independ ently selected from R 24 ; or 20 e C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkenyl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C38 cycloalkenyl-C 1

.

6 -alkyl;

R

22 and R 23 are independently selected from hydrogen, C_ 6 -alkyl, carboxy-C 1

.

6 -alkyl, -C1_e-alkyl-C(O)-O-Cje-alkyl, -C(O)-O-C1.e-alkyl, -C1.e-alkyl-S(O)2-C1.e-alkyl, 25 -C 1

-

6 -alkyl-S(O) 3 H, C 3

-

8 -cycloalkyl, aryl, or heteroaryl; or R 22 and R 2 3 together with the nitro gen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitro gen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 ; 30

R

3 6 and R 37 are independently selected from carboxy-C 1

.

6 -alkyl, -C 1

-

6 -alkyl-C(O)-O-C_ 6 -alkyl, -C(O)-O-C1.

6 -alkyl, -C1.

6 -alkyl-S(O) 2 -C1.

6 -alkyl, C 3

-

8 -cycloalkyl, aryl, or heteroaryl; or R 3 6 and

R

37 together with the nitrogen to which they are attached form a 3 to 8 membered heterocyc lic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two fur- WO 2007/006814 PCT/EP2006/064289 21 ther heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is option ally substituted with one or more substituents independently selected from R 24 ;

R

24 is halogen, nitro, cyano, hydroxy, carboxy, oxo, -CF 3 , C_ 6 -alkyl, hydroxy-C_ 6 -alkyl, car 5 boxy-C_ 6 -alkyl, -C(O)-Cl.

6 -alkyl, -C(O)-C 3 --cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)

C

3

-

8 -heterocyclyl -C(O)-O-C1_ 6 -alkyl, -Cj_ 6 -alkyl-C(O)-O-Cj_ 6 -alkyl, aryl, heteroaryl, aryl-Cl_ 6 alkyl, heteroaryl-Cl_ 6 -alkyl, C 3

-

8 -cycloalkyl, C 3

-

8 -heterocyclyl, C 3

-

8 -cycloalkyl-Cl_ 6 -alkyl, C3-8 heterocyclyl-Cl_ 6 -alkyl, -Cl_ 6 -alkyl-C(O)-C 3

-

8 -heterocyclyl, -C(O)-O-Cl_ 6 -alkyl-aryl,

-NH-S(O)

2

R

28 , or -S(O) 2

R

28 , wherein each cyclic moiety is optionally substituted with one or 10 more substituents independently selected from R 2 9 ;

R

2 5 and R 26 are independently Cl_ 6 -alkyl, halogen, nitro, cyano, hydroxy, -C(O)-O-C 1

,

6 -alkyl, carboxy, -C1.

6 -alkyl-C(O)-O-C 1

.

6 -alkyl, carboxy-C 1

.

6 -alkyl, carboxy-C 3

-

8 -cycloalkyl, -CF 3 , -S(0) 2

CH

3 , or -S(0) 2

NH

2 ; 15

R

2 8 is Cl_ 6 -alkyl, carboxy-C 1

.

6 -alkyl, -C1_ 6 -alkyl-C(O)-O-C_ 6 -alkyl, C 3

-

8 -cycloalkyl, aryl, aryl

C

1

.

6 -alkyl, heteroaryl optionally substituted with C 1

.

6 -alkyl, -NH 2 , or -N(CH 3

)

2 ;

R

29 is halogen, nitro, cyano, hydroxy, carboxy, oxo, -CF 3 , C_ 6 -alkyl, or C_ 6 -alkoxy; 20

R

3 5 is halogen, nitro, cyano, hydroxy, -C(O)-O-C1_ 6 -alkyl, carboxy, -C1_ 6 -alkyl-C(O)-O-C_ 6 alkyl, carboxy-C 1

.

6 -alkyl, -CF 3 , -S(O) 2

CH

3 , or -S(O) 2

NH

2 ; 25 as well as any salt hereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. Embodiment 2. A compound according to embodiment 1 wherein wherein R 1 is C_ 8 -alkyl, C2_ 8 -alkenyl, aryl, heteroaryl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C 3

-

8 -cycloalkyl-C 2

-

6 -alkenyl, C3-8 30 cycloalkenyl-C_ 6 -alkyl, C 3

-

8 -cycloalkenyl-C 2

-

6 -alkenyl, C 3

-

8 -heterocyclyl-C_ 6 -alkyl, C-8 heterocyclyl-C 2

-

6 -alkenyl, C 3

-

8 -heterocycloalkenyl-C_ 6 -alkyl, C 3

-

8 -heterocycloalkenyl-C 2 6 alkenyl, aryl-C_ 6 -alkyl, or aryl-C 2

-

6 -alkenyl, each of which is optionally substituted with one or more substituents R 3 , R 4 , R and R .

WO 2007/006814 PCT/EP2006/064289 22 Embodiment 3. A compound according to embodiment 2 wherein R 1 is C 1

,

8 -alkyl, C28 alkenyl, aryl, heteroaryl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C 3

-

8 -cycloalkyl-C 2

-

6 -alkenyl, C38 cycloalkenyl-C 1

.

6 -alkyl, C 3

-

8 -cycloalkenyl-C 2

-

6 -alkenyl, aryl-C 1

.

6 -alkyl, or aryl-C 2

-

6 -alkenyl, each of which is optionally substituted with one or more substituents R , R 4 , R 5 and R 6 . 5 Embodiment 4. A compound according to embodiment 3 wherein R 1 is C 1

,

8 -alkyl, C28 alkenyl, aryl, heteroaryl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C 3

-

8 -cycloalkenyl-C_ 6 -alkyl, or aryl-C_ 6 alkyl, each of which is optionally substituted with one or more substituents R , R 4 , R 5 and R 6 . 10 Embodiment 5. A compound according to embodiment 4 wherein R 1 is C 1

,

8 -alkyl, C28 alkenyl, phenyl, pyridinyl, benzo[1,3]dioxolyl, C 3

-

8 -cycloalkyl-C_ 6 -alkyl, C 3

-

8 -cycloalkenyl-C_ 6 alkyl, or phenyl-C_ 6 -alkyl, each of which is optionally substituted with one or more substitu ents R 3 , R 4 , R and R 6 . 15 Embodiment 6. A compound according to embodiment 5 wherein R 1 is methyl, ethyl, propyl, butyl, 3-methyl-butyl, 2,2-dimethylpropyl, 1,3,-dimethylbutyl, isopropyl, 3-methyl-but-2-enyl, ethenyl, propenyl, butenyl, cyclopropyl-methyl, cyclopropyl-ethyl, cyclopropyl-propyl, cyclobu tyl-methyl, cyclobutyl-ethyl, cyclobutyl-propyl, cyclopentyl-methyl, cyclopentyl-ethyl, cyclopentyl-propyl, cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl, cycloheptyl 20 methyl, cycloheptyl-ethyl, cycloheptyl-propyl, cyclohexenyl-methyl, cyclohexenyl-ethyl, cyclo hexenyl-propyl, cycloheptenyl-methyl, cycloheptenyl-ethyl, cycloheptenyl-propyl, phenyl, pyridinyl, benzo[1,3]dioxolyl, benzyl, phenethyl, phenyl-propyl, bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each of which is optionally substituted with one or more sub stituents R , R 4 , R 5 and R . 25 Embodiment 7. A compound according to embodiment 6 wherein R 1 is methyl, ethyl, propyl, butyl, 3-methyl-butyl, 2,2-dimethylpropyl, 1,3,-dimethylbutyl, isopropyl, 3-methyl-but-2-enyl, ethenyl, cyclohexyl-methyl, cyclohexyl-ethyl, cyclohexyl-propyl, cyclohexenyl-methyl, cyclo hexenyl-ethyl, cyclohexenyl-propyl, cycloheptenyl-methyl, cycloheptenyl-ethyl, phenyl, 30 pyridinyl, benzo[1,3]dioxolyl, benzyl, phenethyl, phenylpropyl, bicyclo[2.2.1]heptenyl-methyl or bicyclo[2.2.1]heptyl-methyl, each of which is optionally substituted with one or more substituents R , R 4 , R and R .

WO 2007/006814 PCT/EP2006/064289 23 Embodiment 8. A compound according to embodiment 7 wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl or 3-methyl-butyl, each of which is optionally substituted with one or more substituents R , R 4 , R and R 6 . 5 Embodiment 9. A compound according to embodiment 7 wherein R 1 is benzyl, phenethyl or phenylpropyl, optionally substituted with one or more substituents R , R 4 , R and R 6 . Embodiment 10. A compound according to embodiment 7 wherein R 1 is phenyl, optionally substituted with one or more substituents R , R 4 , R 5 and R 6 . 10 Embodiment 11. A compound according to any one of the embodiments 1 to 10 wherein R 2 is C 1

,

8 -alkyl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C 1

.

8 -alkyl or C 3

-

8 -cycloalkenyl, each of which is optionally substituted with one or more substituents R 30 , R 31 , R 32 and R 33 . 15 Embodiment 12. A compound according to embodiment 11 wherein R 2 is C 3

-

8 -cycloalkyl or

C

3

-

8 -cycloalkyl-C_ 8 -alkyl optionally substituted with one or more substituents R 30 , R 31 , R 32 and

R

33 . Embodiment 13. A compound according to embodiment 12 wherein R 2 is C 3

-

8 -cycloalkyl op 20 tionally substituted with one or more substituents R 3 0 , R 31 , R 3 2 and R 3 3 . Embodiment 14. A compound according to embodiment 11 wherein R 2 is methyl, ethyl, pro pyl, butyl, pentyl, hexyl, 3-methylbutyl, 3,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcy 25 clohexyl, or ethylcyclopentyl, each of which may optionally be substituted with R 30 . Embodiment 15. A compound according to embodiment 14 wherein R 2 is methylcyclopentyl or methylcyclohexyl, each of which may optionally be substituted with R 30 . 30 Embodiment 16. A compound according to embodiment 14 wherein R 2 is cyclohexyl option ally substituted with R 30 . Embodiment 17. A compound according to any one of the embodiments 1 to 16 which is WO 2007/006814 PCT/EP2006/064289 24 o 0 \ NN A N A N A HN N 0 HH H R o R 30 wherein A and R 3 0 are as defined in embodiment 1. Embodiment 18. A compound according to any one of the embodiments 1 to 16 which is R0 R N N N J N NA -30 or z3 5 R wherein A, R 3 and R 30 are as defined in embodiment 1. Embodiment 19. A compound according to any one of the embodiments 1 to 16 which is

R

4

R

3 R5 0 RSN N A 10 wherein A, R 3 , R 4 , R 5 and R 30 are as defined in embodiment 1. Embodiment 20. A compound according to any one of the embodiments 1 to 19 wherein R 3 ,

R

4 , R 5 and R 6 are independently selected from the group consisting of * halogen, hydroxy, carboxy, -CF 3 ; or 15 e -NR 10 R; or * C_ 6 -alkyl, C 2

-

6 -alkenyl, C1_ 6 -alkoxy, C 3

-

6 -alkenyloxy, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkoxy,

C

3

-

8 -cycloalkyl-Cl_ 6 -alkyl, C 3

-

6 -cycloalkyClC 1

.

6 -alkoxy, C 3

-

8 -cycloalkenyl-Cl_ 6 -alkoxy, WO 2007/006814 PCT/EP2006/064289 25 phenyl-C_ 6 -alkoxy, each of which is optionally substituted with one or more substitu ents independently selected from R 1 2 ; or * Phenyl, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, or ben zylthio; or 5 e -C(O)-R 27 , -S(O) 2

-R

27 , -C(O)-NR 13

R

1 4 , or -S(O)2-NR1R14; or *two substituents selected from R 3 , R 4 , R 5 and R 6 attached to the same or adjacent atoms together may form a radical -O-(CH 2

)

1

,

3 -O-. Embodiment 21. A compound according to embodiment 20 wherein R 3 , R 4 , R 5 and R 6 , are 10 independently selected from the group consisting of halogen, -CF 3 , Cl_ 6 -alkyl, C 2

-

6 -alkenyl, Cl_ 6 -alkoxy, phenyl, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, benzylthio, phenyl-C_ 6 -alkoxy, C 3

-

8 -cycloalkyl, C3-8 cycloalkoxy, or C 3

-

6 -cycloalkyl-C_ 6 -alkoxy, each of which is optionally substituted with one or more substituents independently selected from R 1 2 ; or -NR 10 R, -C(O)-R 2 7 , -S(O) 2

-R

27 , 15 C(O)-NR R 14 , or -S(O) 2 -NR R 14 . Embodiment 22. A compound according to embodiment 21 wherein R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of halogen, CF 3 , C_ 6 -alkyl, C_ 6 -alkoxy, phenoxy, benzyloxy, phenylthio, benzylthio, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkoxy, or C3-6 20 cycloalkyl-C_ 6 -alkoxy, each of which is optionally substituted with one or more substituents independently selected from R 12 ; or -NR 10

R

1

,-C(O)-R

27 , -S(O) 2

-R

2 7 , -C(O)-NR 13

R

14 , or S(O) 2 -NR R 14 . Embodiment 23. A compound according to embodiment 21 wherein R 3 , R 4 , R 5 and R 6 are 25 independently selected from the group consisting of F, Cl, Br, -CF 3 , methyl, ethyl, propyl, bu tyl, isopropyl, tert-butyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, tert-butoxy, cyclo hexyloxy, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclopropyl-propoxy, cyclobutyl-methoxy, cyclobutyl-ethoxy, cyclobutyl 30 propoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclopentyl-propoxy, cyclohexyl-methoxy, cyclohexyl-ethoxy, cyclohexyl-propoxy, cycloheptyl-methoxy, cycloheptyl-ethoxy, cycloheptyl propoxy, phenylethoxy, phenylthio or benzylthio, each of which is optionally substituted with one or more substituents independently selected from R 1 2 ; or -NR 10 R, -C(O)-R 2 7 , -S(O) 2 R 2 7 , -C(O)-NR R 14 , or -S(O) 2 -NR R 14 . 35 WO 2007/006814 PCT/EP2006/064289 26 Embodiment 24. A compound according to embodiment 23 wherein R 3 , R 4 , R and R 6 are independently selected from the group consisting of F, Cl, Br, -CF 3 , methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylmethoxy, phenylethoxy, 5 phenylthio or benzylthio, each of which is optionally substituted with one or more substituents independently selected from R 12 ; or -NR 10

R

1 , -C(O)-R 27 , -S(O) 2

-R

2 7 , -C(O)-NR 13

R

14 , or S(O) 2 -NR R 14 . Embodiment 25. A compound according to embodiment 24 wherein R 3 , R 4 , R 5 and R 6 are in 10 dependently selected from the group consisting of F, Cl, Br, -CF 3 , methyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, benzyloxy, phenylthio or benzylthio, each of which is optionally substituted with one or more substituents independently selected from R 1 . Embodiment 26. A compound according to embodiment 25 wherein R 3 , R 4 , R 5 and R 6 are 15 independently selected from the group consisting of phenoxy and benzyloxy, each of which is optionally substituted with one or more substituents independently selected from R 1 . Embodiment 27. A compound according to embodiment 25 wherein R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of F, Cl, Br or -CF 3 . 20 Embodiment 28. A compound according to any one of the embodiments 1 to 27 wherein R 30 ,

R

31 , R 3 2 and R 33 are independently selected from the group consisting of * halogen, hydroxy, carboxy, -CF 3 ; or * -NR 10

R

1 ; or 25 e C_ 6 -alkyl, C 2

-

6 -alkenyl, Cl_ 6 -alkoxy, C 3

-

6 -alkenyloxy, C 3

-

8 -cycloalkyl, C3-8 cycloalkoxy, C 3

-

8 -cycloalkyl-C 1

.

6 -alkyl, C 3

-

6 -cycloalkyl-C 1

.

6 -alkoxy, C 3

-

8 -cycloalkenyl Cl_ 6 -alkoxy, each of which is optionally substituted with one or more substituents in dependently selected from R 12 ; or * Phenyl, phenoxy, benzyloxy, indanyloxy, benzo[1,3]dioxolyloxy, phenylthio, or 30 benzylthio; or * -C(O)-R 27 , -S(O) 2

-R

27 , -C(O)-NR 13

R

1 4 , or -S(O) 2

-NR

13

R

1 4 ; or *two substituents selected from R 30 , R 31 , R 32 or R 33 attached to the same or adja cent atoms together may form a radical -O-(CH2)1-3-0-.

WO 2007/006814 PCT/EP2006/064289 27 Embodiment 29. A compound according to embodiment 28 wherein R 30 , R 31 , R 32 and R" 3 are independently selected from the group consisting of halogen, -CF 3 , Cl_ 6 -alkyl, C 2

-

6 -alkenyl, Cl_ 6 -alkoxy, phenoxy, phenyl, benzyloxy, phenylthio, benzylthio, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkoxy, or C 3

-

6 -cycloalkyl-Cl_ 6 -alkoxy, each of which is 5 optionally substituted with one or more substituents independently selected from R 1 2 ; or C(O)-R 27 , -S(O) 2

-R

27 , -C(O)-NR 13

R

14 , or -S(O) 2

-NR

13

R

14 . Embodiment 30. A compound according to embodiment 28 wherein R 30 , R 31 , R 32 and R 33 are independently selected from the group consisting of F, Cl, Br, -CF 3 , methyl, ethyl, propyl, bu 10 tyl, isopropyl, tert-butyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzy loxy, indanyloxy, benzo[1,3]dioxolyloxy, cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclopropyl-propoxy, cyclobutyl-methoxy, cyclobutyl-ethoxy, cyclobutyl-propoxy, cyclopentyl methoxy, cyclopentyl-ethoxy, cyclopentyl-propoxy, cyclohexyl-methoxy, cyclohexyl-ethoxy, 15 cyclohexyl-propoxy, cycloheptyl-methoxy, cycloheptyl-ethoxy, cycloheptyl-propoxy, phenyl thio or benzylthio, each of which is optionally substituted with one or more substituents inde pendently selected from R 1 2 ; or -C(O)-R 27 , -S(O) 2

-R

2 7 , -C(O)-NR 13

R

14 , or -S(O) 2

-NR

13

R

14 . Embodiment 31. A compound according to embodiment 30 wherein R 30 , R 31 , R 32 and R 33 are 20 independently selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, phenyl, phenoxy, benzyloxy, cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclobu tyl-methoxy, cyclobutyl-ethoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclohexyl methoxy, cyclohexyl-ethoxy, each of which is optionally substituted with one or more sub 25 stituents independently selected from R 1 . Embodiment 32. A compound according to embodiment 31 wherein R 30 , R 31 , R 32 and R 33 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, bu 30 toxy, tert-butoxy, benzyloxy, or cyclopropyl-methoxy, each of which is optionally substituted with one or more substituents independently selected from R 1 . Embodiment 33. A compound according to embodiment 32 wherein R 30 , R 31 , R 32 and R 33 are independently selected from the group consisting of methyl or ethyl, each of which is option 35 ally substituted with one or more substituents independently selected from R 1

.

WO 2007/006814 PCT/EP2006/064289 28 Embodiment 34. A compound according to embodiment 32 wherein R 30 , R 31 , R 32 and R" 3 are independently selected from the group consisting of cyclopentyl or cyclohexyl optionally sub stituted with one or more substituents independently selected from R 1 . 5 Embodiment 35. A compound according to any one of the embodiments 1 to 34 wherein R 10 and R" independently represent hydrogen, Cl_ 6 -alkyl, -C(O)-Cl_ 6 -alkyl, carboxy-C 1

.

6 -alkyl, C(O)-C 3

-

8 -cycloalkyl, or -S(O) 2

-C

1

.

6 -alkyl. 10 Embodiment 36. A compound according to embodiment 35 wherein R 1 0 and R" independ ently represent hydrogen, -C(O)-C1.

6 -alkyl, -C(O)-C 3

-

8 -cycloalkyl, or -S(O) 2

-C

1

.

6 -alkyl. Embodiment 37. A compound according to embodiment 35 wherein R 1 0 and R" independ ently represent hydrogen, methyl, ethyl, propyl, butyl, -C(O)-methyl, -C(O)-ethyl, 15 -C(O)-propyl, -C(O)-isopropyl, -C(O)-butyl, -C(O)-cyclopentyl, -S(O) 2 -methyl, carboxy-ethyl, carboxy-propyl or carboxy-butyl. Embodiment 38. A compound according to any one of the embodiments 1 to 37 wherein R 27 is C1.

6 -alkyl, C1.

6 -alkoxy, C 2

-

6 -alkenyl, C 2

-

6 -alkynyl, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C 1

.

6 -alkyl, 20 aryl, aryl-C 1

.

6 -alkyl, aryl-C 2

-

6 -alkenyl, heteroaryl, heteroaryl-Cl_ 6 -alkyl, carboxy-C 1

.

6 -alkyl, C1-6 alkoxy-C 1

.

6 -alkyl, Cl_ 6 -alkylthio-Cl_ 6 -alkyl, R 10

HN-C

1

_

6 -alkyl, R 10 R N-C 1

_

6 -alkyl, R 10 R N-S(O) 2 C 1

.

6 -alkyl, or R 10

R

11

N-C(O)-C

1

_

6 -alkyl, each of which is optionally substituted with one or more substituents independently selected from R 1 . 25 Embodiment 39. A compound according to embodiment 38 wherein R 27 is Cl_ 6 -alkyl, C1_6 alkoxy, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C 1

.

6 -alkyl, aryl-C 1

.

6 -alkyl, aryl-C 2

-

6 -alkenyl, aryl, het eroaryl, heteroaryl-Cl_ 6 -alkyl, carboxy-C 1

.

6 -alkyl, Cl_ 6 -alkoxy-Cl_ 6 -alkyl, R 10

HN-C

1

_

6 -alkyl,

R

10

R

11

N-C

1

_

6 -alkyl, R 10

R

11

N-S(O)

2

-C

1

_

6 -alkyl, or R 1 0

R

11

N-C(O)-C

1

_

6 -alkyl, each of which is op tionally substituted with one or more substituents independently selected from R 1 . 30 Embodiment 40. A compound according to embodiment 39 wherein R 27 is C 1

.

6 -alkyl, C1_6 alkoxy, C 3

-

8 -cycloalkyl, C 3

-

8 -cycloalkyl-C 1

.

6 -alkyl, aryl, heteroaryl-Cl_ 6 -alkyl, aryl-Cl_ 6 -alkyl, Cj_ 6 -alkoxy-C 1

_

6 -alkyl, carboxy-C 1

_

6 -alkyl, or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from R 1 . 35 WO 2007/006814 PCT/EP2006/064289 29 Embodiment 41. A compound according to embodiment 40 wherein R 2 7 is methyl, ethyl, pro pyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole, or thiazole, each of which is optionally substituted with one or more substituents independently selected from R 1 . 5 Embodiment 42. A compound according to embodiment 41 wherein R 27 is methyl, ethyl, pro pyl, n-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, phenyl, pyridyl, thiophene, imidazole, or thiazole. 10 Embodiment 43. A compound according to embodiment 42 wherein R 27 is methyl, ethyl, or propyl. Embodiment 44. A compound according to any one of the embodiments 1 to 43 wherein R 12 is halogen, -CF 3 , -CN, C-_-alkyl, C-_-alkoxy, C-_-alkylthio, C 26 -alkenyloxy, C,3 15 cycloalkyloxy, C 3

-

8 -cycloalkenyloxy, aryloxy, aryl-C 1

.

6 -alkoxy, aryl-C 1

.

6 -alkenyloxy, C3.-8 cycloalkyl-C 1

.

6 -alkoxy, C 3

-

8 -cycloalkyl-C 1

.

6 -alkenyloxy, C 3

-

8 -heterocyclyl-C_ 6 -alkoxy, or C3-8 heterocyclyl-C_ 6 -alkenyloxy, each of which is optionally substituted with one or more sub stituents independently selected from R 38 ; or NR 1 0

R

1 , or -S(O) 2

-C

1

_

6 -alkyl. 20 Embodiment 45. A compound according to embodiment 44 wherein R 1 2 is halogen, -CF 3 , CN, C_ 6 -alkyl, C_ 6 -alkoxy, C_ 6 -alkylthio, C 3

-

8 -cycloalkyloxy, aryloxy, aryl-C_ 6 -alkoxy, C-8 cycloalkyl-C 1

.

6 -alkoxy, or C 3

-

8 -heterocyclyl-C_ 6 -alkoxy, each of which is optionally substituted with one or more substituents independently selected from R 3 8 ; or NR 1 0

R

1 , or -S(O) 2

-C

1

_

6 alkyl. 25 Embodiment 46. A compound according to embodiment 45 wherein R 1 2 is F, Cl, Br, -CF 3 , CN, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, propoxy, butoxy, phenoxy, benzyloxy, cyclopropyl-methoxy, cyclopropyl-ethoxy, cyclobutyl-methoxy, cyclobutyl-ethoxy, cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclohexyl-methoxy, cyclohexyl 30 ethoxy, -NHC(O)CH 3 , or -S(O) 2

-CH

3 . Embodiment 47. A compound according to embodiment 46 wherein R 1 2 is F, Cl, Br, -CF 3 , CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, NHC(O)CH 3 , or -S(O) 2

-CH

3 . 35 WO 2007/006814 PCT/EP2006/064289 30 Embodiment 48. A compound according to embodiment 47 wherein R" is F, Cl, Br, methyl or ethyl. Embodiment 49. A compound according to any one of the embodiments 1 to 48 wherein R 13 5 and R 14 are independently selected from hydrogen and C_e-alkyl; or R" and R 1 4 together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen atom. Embodiment 50. A compound according to any one of the embodiments 1 to 49 wherein R 15 10 is selected from F, Cl, Br, hydroxy, carboxy, -CF 3 , or C 1

,

6 -alkyl. Embodiment 51. A compound according to any one of the embodiments 1 to 50 wherein R 3 1 is F, Cl, Br, methyl or ethyl. 15 Embodiment 52. A compound according to any one of the embodiments 1 to 51 wherein A is R 7R 7R7 N N N N N-N S S or S Embodiment 53. A compound according to embodiment 52 wherein A is R 7R7 )-R 8 \ NI\ R 8 or\( \ S R 8 SS S o 20 Embodiment 54. A compound according to embodiment 53 wherein A is

R

8 S Embodiment 55. A compound according to any one of the embodiments 1 to 54 wherein A is 25 substituted with at least one substituent R 7 , R 8 or R 9 independently selected from e Cl_ 6 -alkyl, Cl_ 6 -alkylthio, C 3

-

6 -cycloalkylthio, each of which is substituted with one or more substituents independently selected from R 34 ; or WO 2007/006814 PCT/EP2006/064289 31 S -C 1

_

6 -alkyl-NR 1 9

R

2 0 , -S(O) 2

-R

21 , -S(O) 2

-NR

19

R

2 0 , or -S(O) 2

-N(R

1 9 )(C1_ 6 -alkyl)

C(O)-NR

22

R

2 3 , each of which is substituted with one or more substituents inde pendently selected from R 25 ; or * -C(O)-O-Cl_ 6 -alkyl, C 3

-

6 -cycloalkyl-C_ 6 -alkylthio, or carboxy-C 1

.

6 -alkyl, each 5 of which is optionally substituted with one or more substituents independently se lected from R 1 6 ; or e C 3

-

8 -cycloalkyl or C 3

-

8 -cycloalkylthio, each of which is optionally substituted on the cycloalkyl part with one or more substituents independently selected from

R

1 8 ; or 10 e -C 1

_

6 -alkyl-NR 3 6

R

3 7 , or -S(O) 2

-NR

36

R

3 7 , each optionally substituted with one or more substituents independently selected from R 25 ; or * -Cl_-alkyl-C(O)NR 36

R

37 , or -Cl_ 6 -alkyl-NH-C(O)-C_ 6 -alkyl-NR 2 2

R

23 , each op tionally substituted with one or more substituents independently selected from

R

26 . 15 Embodiment 56. A compound according to embodiment 55 wherein A is substituted with at least one substituent R 7 , R 8 or R 9 independently selected from e C 1

,

6 -alkyl, C_ 6 -alkylthio substituted with one or more substituents inde 20 pendently selected from R 34 ; or * -S(O) 2

-R

21 , -S(O) 2

-NR

19

R

20 , or -S(O) 2

-N(R

19

)(C

1

_

6 -alkyl)-C(O)-NR 2 2

R

2 3 ; or * -C(O)-O-C 1

_

6 -alkyl, which is optionally substituted with one or more sub stituents independently selected from R 16 . 25 Embodiment 57. A compound according to embodiment 56 wherein A is substituted with at least one substituent R 7 , R 8 or R 9 independently selected from e methylthio, ethylthio, propylthio, isopropylthio,butylthio or 2 methylpropylthio, each of which is substituted with one or more substituents inde 30 pendently selected from R 34 ; or e -S(O) 2 -R , -S(O) 2

-NR

19

R

20 , or -S(O) 2

-N(R

19

)-CH

2 -C(O)-NR R 23 . Embodiment 58. A compound according to embodiment 57 wherein A is substituted with at least one substituent R 7 , R 8 or R 9 independently selected from WO 2007/006814 PCT/EP2006/064289 32 e methylthio, isopropylthio, ethylthio, or 2-methylpropylthio each of which is substituted with one or more substituents independently selected from R 34 . Embodiment 59. A compound according to embodiment 57 wherein R 7 , R 8 or R 9 are inde 5 pendently selected from -S(O) 2

-R

21 . Embodiment 60. A compound according to any one of the embodiments 1 to 59 wherein if more than one substituent R 7 , R 8 and R 9 is present on A that additional R 7 , R 8 and R 9 may be selected from methyl, ethyl, propyl, butyl, Cl, F, or Br. 10 Embodiment 61. A compound according to any one of the embodiments 1 to 60 wherein R 16 ,

R

1 7 , and R 1 8 are independently halogen, carboxy, or carboxy-C 1

.

6 -alkyl. Embodiment 62. A compound according to any one of the embodiments 1 to 61 wherein R 34 15 is carboxy, carboxy-C 1

.

6 -alkyl, or -C(O)-O-C 1

.

6 -alkyl. Embodiment 63. A compound according to embodiment 62 wherein R 34 is carboxy. Embodiment 64. A compound according to any one of the embodiments 1 to 63 wherein R 19 20 and R 2 0 independently represent hydrogen, C 1

,

6 -alkyl or carboxy-C 1

.

6 -alkyl, or R 1 9 and R 20 together with the nitrogen to which they are attached form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, the heterocyclic ring is optionally substituted with one or more substituents independently selected from R 24 . 25 Embodiment 65. A compound according to any one of the embodiments 1 to 64 wherein R 21 is selected from C 1

.

6 -alkyl or carboxy-C 1

.

6 -alkyl. Embodiment 66. A compound according to any one of the embodiments 1 to 65 wherein R 22 30 and R 2 3 are independently selected from C 1

,

6 -alkyl. Embodiment 67. A compound according to any one of the embodiments 1 to 66 wherein R 36 and R 3 7 are independently selected from carboxy-C 1

.

6 -alkyl.

WO 2007/006814 PCT/EP2006/064289 33 Embodiment 68. A compound according to any one of the embodiments 1 to 67 wherein R1 4 is carboxy or carboxy-C 1

.

6 -alkyl. Embodiment 69. A compound according to any one of the embodiments 1 to 68 wherein R 25 5 and R 2 6 are independently selected from carboxy or carboxy-C 1

.

6 -alkyl. Embodiment 70. A compound according to any one of the embodiments 1 to 69 wherein R 28 is C1.

6 -alkyl, carboxy-C 3

-

8 -cycloalkyl or carboxy-C 1

.

6 -alkyl. 10 Embodiment 71. A compound according to any one of the embodiments 1 to 70 wherein R 29 is F, Cl, Br or carboxy. Embodiment 72. A compound according to any one of the embodiments 1 to 71 wherein R 35 is F, Cl, Br or carboxy. 15 In another embodiment, the present invention provides a novel compound wherein the com pound is selected from the following: [2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid; [2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid; 20 {2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclohexyl-3-(2,2-dimethyl-propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(2-Cyclohex-1 -enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; [2-(3-Bicyclo[2.2.1 ]hept-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid; 25 [2-(3-Bicyclo[2.2.1 ]hept-5-en-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl] acetic acid; {2-[3-Cyclohexyl-3-(2-cyclohexyl-ethyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid; 3-[2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid; 30 3-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid; 3-{2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-Butyl-3-( trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-propionic acid; WO 2007/006814 PCT/EP2006/064289 34 3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-(2-Cyclohex-1 -enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid; 5 {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(2-Cyclohex-1 -enyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5 10 ylsulfanyl}-acetic acid; {2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 3-{2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 15 {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 20 3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-propionic acid; 3-{2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 25 propionic acid; 2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2 methyl-propionic acid; 2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-2-methyl propionic acid; 30 {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonylaminol-acetic acid; 3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonylamino}-propionic acid; (Methyl-{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 35 sulfonyl}-amino)-acetic acid; WO 2007/006814 PCT/EP2006/064289 35 (S)-1 -{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyl}-pyrrolidine-2-carboxylic acid; {2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 5 {2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 3-{2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll 10 propionic acid; {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Methyl-butyl)-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 15 {2-[3-(trans-4-tert-Butoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(trans-4-Cyclopropylmethoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[trans-4-(2-Methoxy-ethoxy)-cyclohexyl]-3-(3-methyl-butyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid; {2-[3-(trans-4-Benzyloxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid ; 25 {2-[3-(trans-4-Ethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid ; {2-[3-(trans-4-Cyclopropylmethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid; {2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 30 {2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid ; {2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 3-{2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}- propionic acid; 2-[3-(4-trans-Ethyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll acetic acid ; WO 2007/006814 PCT/EP2006/064289 36 {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(4-phenoxy-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid ; 3-{2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll propionic acid ; 5 2-Methyl-2-{2-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-propionic acid; 2-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid; 5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazole-2 10 carboxylic acid ethyl ester; {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-acetic acid ethyl ester; 2-Methyl-2-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4 thiadiazol-2-ylsulfanyl}-propionic acid; 15 {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-acetic acid; 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyll-propionic acid ethyl ester; 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl} 20 propionic acid methyl ester; {2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 2-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2-methyl-propionic acid; 25 3-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-propionic acid; 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazo-2-yl} 30 propionic acid; {2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(2-Isopropoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; WO 2007/006814 PCT/EP2006/064289 37 {2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 5 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1 -trifluoromethyl-ethoxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid; {2-[3-(2-Ethoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 10 acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid; {2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 15 3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 3-{2-[3-(2-Iso-propoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 3-{2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-propionic acid; 3-{2-[3-(2-Cyclohexyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1 -trifluoromethyl-ethoxy) ethyl]-ureido}-thiazol-5-ylsulfanyl)-propionic acid; 25 3-{2-[3-(2-Iso-butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol 5-ylsulfanyl)-propionic acid; 3-{2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 30 ylsulfanyl}-propionic acid; {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; WO 2007/006814 PCT/EP2006/064289 38 {2-[3-(3-Methoxy-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(3-Benzyloxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 5 3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; {2-[3-(2-Benzyloxy-1 -methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 10 ylsulfanyl}-acetic acid; {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 3-{2-[3-(2-Benzyloxy-1 -methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; 15 3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; {2-[3-[2-(2-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[2-(3-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid; {2-[3-[2-(4-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[2-(2-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 25 {2-[3-[2-(3-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(1 -phenyl-ethoxy)-ethyl]-ureido}-thiazol-5 30 ylsulfanyl)-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethylsulfanyl-benzyloxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid; {2-[3-[2-(2-Cyano-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; WO 2007/006814 PCT/EP2006/064289 39 {2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid; {2-[3-[2-(4-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 5 {2-[3-[2-(2-Fluoro-6-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid; {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] 10 thiazol-5-ylsulfanyl}-acetic acid; {2-[3-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-p-tolyl-ethyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 15 {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-pentafluorophenylmethoxy-ethyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; {2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid; {2-[3-[2-(4-Isopropoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-propoxy-phenyl)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid; 25 {2-[3-[2-(2-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid; {2-[3-[2-(3-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid; {2-[3-[2-(4-Isopropyl-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 30 ylsulfanyl}-acetic acid; {2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid; {2-[3-[2-(3-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; WO 2007/006814 PCT/EP2006/064289 40 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethyl-benzyloxy)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; {2-[3-[2-(4-Methanesulfonyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid; 5 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-benzyloxy)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; {2-[3-[2-(2-Methoxy-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 10 5-ylsulfanyl}-acetic acid; {2-[3-[2-(4-tert-Butyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethoxy-benzyloxy)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; 15 {2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[2-(4-Isopropyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[2-(4-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; {2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 25 {2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[2-(2,3-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[2-(2,6-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 30 5-ylsulfanyl}-acetic acid; {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-[3-(4-Methoxy-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; WO 2007/006814 PCT/EP2006/064289 41 {2-[3-[3-(4-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[3-(Indan-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 5 {2-[3-[3-(3,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[3-(2,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[3-(4-tert-Butyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 10 5-ylsulfanyl}-acetic acid; {2-[3-[3-(4-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[3-(3-Acetylamino-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid; 15 {2-[3-[3-(2-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-[3-(3-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid; {2-[3-[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido] 20 thiazol-5-ylsulfanyl}-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(4-trifluoromethoxy-phenoxy)-propyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(3-trifluoromethoxy-phenoxy)-propyl]-ureidol thiazol-5-ylsulfanyl)-acetic acid; 25 {2-[3-[3-(3-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-propionic acid; 3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 30 5-ylsulfanyll-propionic acid; {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 2-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2 35 methyl-propionic acid; WO 2007/006814 PCT/EP2006/064289 42 2-({2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl} methyl-amino)-N,N-diethyl-acetamide; (S)-1 -{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl} pyrrolidine-2-carboxylic acid; 5 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino} acetic acid; 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylaminol propionic acid; {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 10 acid; {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 2-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyll 2-methyl-propionic acid; 15 (S)-1 -{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 sulfonyl}-pyrrolidine-2-carboxylic acid; {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 sulfonylaminol-acetic acid; 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 20 sulfonylamino}-propionic acid; 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyll propionic acid; 25 {2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; 3-{2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll propionic acid; {2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5 30 ylsulfanyl}-acetic acid; 3-{2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; {2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; WO 2007/006814 PCT/EP2006/064289 43 3-{2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll propionic acid; {2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 5 3-{2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid; {2-[3-Cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ysulfanyl} acetic acid; {2-[3-Cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic 10 acid; {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 15 {2-[3-Cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-Cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic 20 acid; {2-[3-Cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-Cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 25 {2-[3-(6-Acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; 30 {2-[3-(3-Acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; WO 2007/006814 PCT/EP2006/064289 44 {2-[3-(3-Acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-Cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 5 [2-(3-Benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid; {2-[3-Cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll 10 acetic acid; {2-[3-Cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 15 (2-{3-[3-(Azetidine-1 -carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5 ylsulfanyl)-acetic acid; {2-[3-(3,4-Difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid ; {2-[3-(3,4-Difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid; {2-[3-(4-tert-Butyl-cyclohexylmethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; 25 {2-[3-(3-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic 30 acid; {2-[3-Cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; WO 2007/006814 PCT/EP2006/064289 45 {2-[3-(2-Cyclopentylethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3,4-Difluoro-phenyl)-3-( trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 5 {2-[3-(3-Acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-Cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyll 10 acetic acid; (2-{3-[3-(Cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol 5-ylsulfanyl)-acetic acid; {2-[3-(trans-4-Methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 15 {2-[3-Cyclohexylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ysulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclopentylmethyl-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic 20 acid; {2-[3-(3-Chloro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid, {2-[3-Cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; 25 {2-[3-Cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-Cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(3-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} 30 acetic acid, {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid; WO 2007/006814 PCT/EP2006/064289 46 {2-[3-Cyclopentylmethyl-3-(4-isopropoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid; 5 {2-[3-(3-Chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid; {2-[3-(3-Chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-Cyclopentylmethyl-3-(2-fluoro-3-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} 10 acetic acid; {2-[3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}- acetic acid; (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(3,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid; 15 (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,4,5-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid; (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,3,4-trifluoro-phenyl)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid; 2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 20 5-ylsulfanyl}-2-methyl-propionic acid; 2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-2-methyl-propionic acid; {2-[3-(2-Chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ysulfanyl} acetic acid; 25 {2-[3-(3-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(4-Bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} acetic acid; {2-[3-(2-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-Cyclopentylmethyl-3-(3-methoxy-5-trifluoromethyl-phenyl)-ureido]-thiazol-5 30 ylsulfanyl}-acetic acid; {2-[3-(3-Acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid; {2-[3-(1 -Acetyl-2,3-dihydro-1 H-indol-6-yl)-3-cyclopentylmethyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid; {2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll-acetic 35 acid; WO 2007/006814 PCT/EP2006/064289 47 {2-[3-[2-(2-Methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyll-acetic acid; {2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyll-acetic acid; 5 {2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyll-acetic acid; (2-{3-(4-Methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido}-thiazole 5-sulfonyl)-acetic acid; {2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] 10 thiazole-5-sulfonyl}-acetic acid; {2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] thiazole-5-sulfonyl}-acetic acid; {2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyll-acetic acid; 15 2-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-2 methyl-propionic acid; 2-Methyl-2-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] thiazole-5-sulfonyll-propionic acid; 2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 20 sulfonyl}-2-methyl-propionic acid; 2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyl}-2-methyl-propionic acid; 2-Methyl-2-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl] ureido}-thiazole-5-sulfonyl)-propionic acid; 25 2-{2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl) ureido]-thiazole-5-sulfonyl}-2-methyl-propionic acid; 2-{2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyl}-2-methyl-propionic acid; {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5-sulfonyll-acetic 30 acid; 2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazole-5 sulfonyll-propionic acid; {2-[3-(4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyll-acetic acid; {2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 35 sulfonyll-acetic acid; WO 2007/006814 PCT/EP2006/064289 48 {2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole 5-sulfonyl}-acetic acid; {2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll acetic acid; 5 2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazole-5-sulfonyl} propionic acid; 2-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5 sulfonyl}-2-methyl-propionic acid; 2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] 10 thiazole-5-sulfonyl}-2-methyl-propionic acid; 2-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] thiazole-5-sulfonyl}-2-methyl-propionic acid; 3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2 dimethyl-propionic acid; 15 3-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2,2-dimethyl-propionic acid; 2,2-Dimethyl-3-{2-[3-[2-(2-methyl-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyll-propionic acid; 3-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-2,2-dimethyl-propionic acid; 2,2-Dimethyl-3-(2-{3-(4-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-propionic acid; 2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazo-5 ylsulfanyl}-propionic acid; 25 3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2,2-dimethyl-propionic acid; 3-{2-[3-[3-(3-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2,2-dimethyl-propionic acid; 3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 30 ylsulfanyl}-2,2-dimethyl-propionic acid; 2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl} propionic acid; 3-{2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2,2-dimethyl-propionic acid; WO 2007/006814 PCT/EP2006/064289 49 3-{2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2,2-dimethyl-propionic acid; 3-{2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid; 5 {2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 2-methyl-propionic acid; {2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll 10 acetic acid; 2-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll 2-methyl-propionic acid; 3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 2,2-dimethyl-propionic acid; 15 3-{2-[3-(2-Benzylsulfanyl-ethyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll 2,2-dimethyl-propionic acid; 2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido] thiazol-5-ylsulfanyll-propionic acid; 2,2-Dimethyl-3-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido] 20 thiazole-5-sulfonyl}-propionic acid; {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazol-5-ylsulfanyll acetic acid; 2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-uredo]-thiazol-5 ylsulfanyl}-propionic acid; 25 {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole-5-sulfonyll acetic acid; 2-Methyl-2-{2-[3-(4-methyl-cyclohexyl)-3-(3-phenylsulfanyl-propyl)-ureido]-thiazole 5-sulfonyl}-propionic acid; or a pharmaceutically acceptable salt thereof. 30 In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of the present invention, or a pharmaceutically acceptable salt thereof.

WO 2007/006814 PCT/EP2006/064289 50 In another embodiment, the present invention provides a novel method of treating type 2 dia betes, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. 5 In one aspect the invention provides a method of preventing hypoglycaemia comprising ad ministration of a compound according to the present invention. In another aspect the invention provides the use of a compound according to the present in vention for the preparation of a medicament for the prevention of hypoglycaemia. 10 In another aspect the invention provides a compound as described herein, which is an agent useful for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, insulin resistance syndrome, syndrome X, type 2 diabetes, type 1 diabetes, dyslipide mia, hypertension, and obesity. 15 In another aspect the invention provides a compound as described herein for use as a me dicament. In another aspect the invention provides a compound as described herein for treatment of 20 hyperglycemia, for treatment of IGT, for treatment of Syndrome X, for treatment of type 2 diabetes, for treatment of type 1 diabetes, for treatment of dyslipidemia, for treatment of hy perlipidemia, for treatment of hypertension, for treatment of obesity, for lowering of food in take, for appetite regulation, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins, such as GLP-1. 25 In another aspect the invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound as described herein together with one or more pharmaceutically acceptable carriers or excipients. 30 In one embodiment such a pharmaceutical composition may be in unit dosage form, compris ing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the present invention.

WO 2007/006814 PCT/EP2006/064289 51 In another aspect the invention provides the use of a compound according to the invention for increasing the activity of glucokinase. In another aspect the invention provides the use of a compound according to the invention for the preparation of a medicament for the treatment of metabolic disorders, for blood glu 5 cose lowering, for the treatment of hyperglycemia, for the treatment of IGT, for the treatment of Syndrome X, for the treatment of impaired fasting glucose (IFG), for the treatment of type 2 diabetes, for the treatment of type 1 diabetes, for delaying the progression of impaired glu cose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for the treatment of dyslipidemia, for the 10 treatment of hyperlipidemia, for the treatment of hypertension, for lowering of food intake, for appetite regulation, for the treatment of obesity, for regulating feeding behaviour, or for en hancing the secretion of enteroincretins. In another aspect the invention provides the use of a compound according to the invention for the preparation of a medicament for the adjuvant treatment of type 1 diabetes for preventing the onset of diabetic complications. 15 In another aspect the invention provides the use of a compound according to the invention for the preparation of a medicament for increasing the number and/or the size of beta cells in a mammalian subject, for treatment of beta cell degeneration, in particular apoptosis of beta cells, or for treatment of functional dyspepsia, in particular irritable bowel syndrome. 20 In one embodiment the invention provides any of the above uses in a regimen which com prises treatment with a further antidiabetic agent. In a further aspect the invention provides the use of a compound according to the invention or a pharmaceutical composition as described above for the treatment of metabolic disor 25 ders, for blood glucose lowering, for the treatment of hyperglycemia, for treatment of IGT, for treatment of Syndrome X, for the treatment of impaired fasting glucose (IFG), for treatment of type 2 diabetes,for treatment of type 1 diabetes, for delaying the progression of impaired glu cose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treatment of dyslipidemia, for treat 30 ment of hyperlipidemia, for treatment of hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins.

WO 2007/006814 PCT/EP2006/064289 52 In a further aspect the invention provides the use of a compound according to the invention or a pharmaceutical composition as described above for the adjuvant treatment of type 1 diabetes for preventing the onset of diabetic complications. 5 In a further aspect the invention provides the use of a compound according to the invention or a pharmaceutical composition as described above for increasing the number and/or the size of beta cells in a mammalian subject, for treatment of beta cell degeneration, in particu lar apoptosis of beta cells, or for treatment of functional dyspepsia, in particular irritable bowel syndrome. 10 In another embodiment the invention provides a for the treatment of a glucokinase-deficiency mediated condition/disease which is caused by a glucokinase mutation. In another embodiment the invention provides a method wherein the glucokinase-deficiency 15 mediated condition/disease is Maturity-Onset Diabetes of the Young, Neonatal Diabetes Mel litus, or Persistent Neonatal Diabetes Mellitus. In another embodiment the invention provides a method for preventing or ameliorating the development of diabetes in subjects exhibiting symptoms of Impaired Glucose Tolerance, 20 Gestational Diabetes Mellitus, Polycystic Ovarian Syndrome, Cushings syndrome or Meta bolic Syndrome comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. 25 In another embodiment the invention provides a method for preventing or ameliorating mi crovascular diseases comprising administering to a subject in need of such treatment a com pound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method for preventing macrovascular dis 30 eases in subjects exhibiting symptoms of Impaired Glucose Tolerance, Gestational Diabetes Mellitus, or Metabolic Syndrome, comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof, alone or in combination with lipid-lowering drugs, wherein blood glucose normalization oc curs with reduced risk of hypoglycemia. 35 WO 2007/006814 PCT/EP2006/064289 53 In another embodiment the invention provides a method for the preservation of beta-cell mass and function comprising administering to a subject in need of such treatment a com pound according to the invention or pharmaceutical composition thereof, wherein blood glu cose normalization occurs with reduced risk of hypoglycemia. 5 In another embodiment the invention provides a method for preventing amyloid beta peptide induced cell death comprising administering to a subject in need of such treatment a com pound according to the invention or pharmaceutical composition thereof, wherein blood glu cose normalization occurs with reduced risk of hypoglycemia. 10 In another embodiment the invention provides a method wherein the subject is a veterinary subject. In another embodiment the invention provides a method wherein a compound according to 15 the invention is administered as a food additive. In another embodiment the invention provides a method for the treatment of hepatic condi tions benefiting from blood glucose normalization comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composi 20 tion thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method for the treatment of hepatic condi tions benefiting from improved liver function comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition 25 thereof. In another embodiment the invention provides a method for the treatment of hyperglycemic conditions that result from critical illness, or as a consequence of therapeutic intervention comprising administering to a subject in need of such treatment a compound according to the 30 invention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method for the treatment of hepatic condi tions that result from critical illness like cancer, or are a consequence of therapy, for example WO 2007/006814 PCT/EP2006/064289 54 cancer therapy or HIV-treatment, comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method of treatment adjuvant to insulin in 5 insulin-requiring diabetes type 2, or as replacement for insulin comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypo glycemia. 10 In another embodiment the invention provides a method for the treatment of lipodistrophy comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. 15 In another embodiment the invention provides a method for the treatment of hyperglycemia resulting from severe physical stress without signs of liver failure comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceuti cal composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. 20 In another embodiment the invention provides a method wherein the severe physical stress is multiple trauma, or diabetic ketoacidosis. In another embodiment the invention provides a method for preventing apoptotic liver dam 25 age comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method for preventing hypoglycemia com prising administering to a subject in need of such treatment a compound according to the in 30 vention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method for increasing beta-cell mass and function comprising administering to a subject in need of such treatment a compound accord- WO 2007/006814 PCT/EP2006/064289 55 ing to the invention or pharmaceutical composition thereof, wherein blood glucose normaliza tion occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method of preventing type 1 diabetes com 5 prising administering to a subject in need of such treatment a compound according to the in vention or pharmaceutical composition thereof, wherein blood glucose normalization occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method of preserving and/or increasing 10 beta-cell mass and function in patients having undergone pancreatic islet transplantation comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method of improving glucose control during 15 and after surgery comprising administering to a subject in need of such treatment a com pound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method of improving liver function and /or survival in patients undergoing liver transplantation comprising administering to a subject in 20 need of such treatment a compound according to the invention or pharmaceutical composi tion thereof. In another embodiment hereof the invention provides a method wherein the ad ministration occurs before, during or after transplantation, or any combination thereof. In another embodiment the invention provides a method of obtaining blood glucose normali 25 zation comprising administering to a subject in need of such treatment a compound accord ing to the invention or pharmaceutical composition thereof, wherein blood glucose normaliza tion occurs with reduced risk of hypoglycemia. In another embodiment the invention provides a method of preventing or ameliorating dia 30 betic late complications comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof. In another embodiment the invention provides a method of treating type 1 or 2 diabetes comprising administering to a subject in need of such treatment a compound according to the WO 2007/006814 PCT/EP2006/064289 56 invention or pharmaceutical composition thereof, wherein the treatment does not result in a weight gain. In another embodiment the invention provides a method of preventing diabetic ketoacidosis 5 comprising administering to a subject in need of such treatment a compound according to the invention or pharmaceutical composition thereof. COMBINATION TREATMENT 10 In a further aspect of the present invention the present compounds are administered in com bination with one or more further active substances in any suitable ratios. Such further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes. 15 Suitable antidiabetic agents include insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by ref erence, as well as orally active hypoglycemic agents. Suitable orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, a 20 glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the pan creatic p-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, potassium channel openers, such as ormitiglinide, potassium channel blockers such as nateglinide or BTS-67582, glucagon antagonists such as those disclosed in WO 99/01423 25 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), all of which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (protein tyrosine phos phatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis 30 and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) in hibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, and PPAR (peroxisome proliferator activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1 268 or LG-1 069.

WO 2007/006814 PCT/EP2006/064289 57 In one embodiment of the present invention, the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibencla mide, glipizide, glimepiride, glicazide or glyburide. 5 In one embodiment of the present invention, the present compounds are administered in combination with a biguanide eg metformin. In one embodiment of the present invention, the present compounds are administered in combination with a meglitinide eg repaglinide or senaglinide/nateglinide. In one embodiment of the present invention, the present compounds are administered in 10 combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/Cl-1 037 or T 174 or the compounds disclosed in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference. 15 In one embodiment of the present invention the present compounds may be administered in combination with an insulin sensitizer eg such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-1 6336, AR-H049020, LY510929, MBX-1 02, CLX 0940, GW-501516 or the compounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) 20 and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated herein by reference. In one embodiment of the present invention the present compounds are administered in combination with an a-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose. 25 In one embodiment of the present invention the present compounds are administered in combination with a glycogen phosphorylase inhibitor eg the compounds described in WO 97/09040 (Novo Nordisk A/S). In one embodiment of the present invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the pancreatic 30 p-cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide. In one embodiment of the present invention the present compounds are administered in combination with nateglinide. In one embodiment of the present invention the present compounds are administered in combination with an antihyperlipidemic agent or a antilipidemic agent eg cholestyramine, WO 2007/006814 PCT/EP2006/064289 58 colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothy roxine. Furthermore, the compounds according to the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents. 5 Such agents may be selected from the group consisting of CART (***e amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC3 (melanocortin 3) agonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing fac tor binding protein) antagonists, urocortin agonists, P3 adrenergic agonists such as CL 10 316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin reuptake inhibitors (fluoxetine, seroxat or citalopram), serotonin and norepinephrine reuptake inhibitors, 5HT (serotonin) agonists, bombesin ago nists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lac 15 togen, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) ago nists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modula tors, TR P agonists, adrenergic CNS stimulating agents, AGRP (agouti related protein) inhibi tors, H3 histamine antagonists such as those disclosed in WO 00/42023, WO 00/63208 and 20 WO 00/64884, which are incorporated herein by reference, exendin-4, GLP-1 agonists, ciliary neurotrophic factor, and oxyntomodulin. Further antiobesity agents are bupropion (an tidepressant), topiramate (anticonvulsant), ecopipam (dopamine D1/D5 antagonist) and naltrexone (opioid antagonist). In one embodiment of the present invention the antiobesity agent is leptin. 25 In one embodiment of the present invention the antiobesity agent is a serotonin and norepi nephrine reuptake inhibitor eg sibutramine. In one embodiment of the present invention the antiobesity agent is a lipase inhibitor eg orl istat. In one embodiment of the present invention the antiobesity agent is an adrenergic CNS 30 stimulating agent eg dexamphetamine, amphetamine, phentermine, mazindol phendi metrazine, diethylpropion, fenfluramine or dexfenfluramine. Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are p-blockers such as alpre nolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting en 35 zyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and WO 2007/006814 PCT/EP2006/064289 59 ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni modipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Phar macy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. 5 In one embodiment of the present invention, the present compounds are administered in combination with insulin, insulin derivatives or insulin analogues. In one embodiment of the invention the insulin is an insulin derivative is selected from the group consisting of B29-NE-myristoyl-des(B30) human insulin, B29-NE-palmitoyl-des(B30) human insulin, B29-NE-myristoyl human insulin, B29-NE-palmitoyl human insulin, B28-NE 10 myristoyl LysB 28 ProB 2 9 human insulin, B28-NE-palmitoyl LysB 28 ProB 29 human insulin, B30-NE myristoyl-ThrB 29 LysB 3 0 human insulin, B30-NE-palmitoyl-ThrB 29 LysB 3 0 human insulin, B29-NE (N-palmitoyl-y-glutamyl)-des(B30) human insulin, B29-NE-(N-lithocholyl-y-glutamyl)-des(B30) human insulin, B29-NE-(o-carboxyheptadecanoyl)-des(B30) human insulin and B29-NE-(O carboxyheptadecanoyl) human insulin. 15 In another embodiment of the invention the insulin derivative is B29-NE-myristoyl-des(B30) human insulin. In a further embodiment of the invention the insulin is an acid-stabilised insulin. The acid stabilised insulin may be selected from analogues of human insulin having one of the follow ing amino acid residue substitutions: 20 A21G A21G, B28K, B29P A21G, B28D A21G, B28E A21G, B3K, B29E 25 A21G,desB27 A21G, B9E A21G, B9D A21G, B10E insulin. In a further embodiment of the invention the insulin is an insulin analogue. The insulin ana 30 logue may be selected from the group consisting of An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala and position B29 is Lys or Pro; and des(B28-B30), des(B27) or des(B30) human insulin.

WO 2007/006814 PCT/EP2006/064289 60 In another embodiment the analogue is an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro. In another embodiment the analogue is des(B30) human insulin. 5 In another embodiment the insulin analogue is an analogue of human insulin wherein posi tion B28 is Asp. In another embodiment the analogue is an analogue wherein position B3 is Lys and position B29 is Glu or Asp. In another embodiment the GLP-1 derivative to be employed in combination with a com 10 pound of the present invention refers to GLP-1 (1 -37), exendin-4(1-39), insulinotropic frag ments thereof, insulinotropic analogues thereof and insulinotropic derivatives thereof. Insuli notropic fragments of GLP-1 (1-37) are insulinotropic peptides for which the entire sequence can be found in the sequence of GLP-1 (1-37) and where at least one terminal amino acid has been deleted. Examples of insulinotropic fragments of GLP-1 (1-37) are GLP-1 (7-37) 15 wherein the amino acid residues in positions 1-6 of GLP-1 (1-37) have been deleted, and GLP-1 (7-36) where the amino acid residues in position 1-6 and 37 of GLP-1 (1-37) have been deleted. Examples of insulinotropic fragments of exendin-4(1-39) are exendin-4(1-38) and exendin-4(1-31). The insulinotropic property of a compound may be determined by in vivo or in vitro assays well known in the art. For instance, the compound may be administered to an 20 animal and monitoring the insulin concentration over time. Insulinotropic analogues of GLP 1(1-37) and exendin-4(1-39) refer to the respective molecules wherein one or more of the amino acids residues have been exchanged with other amino acid residues and/or from which one or more amino acid residues have been deleted and/or from which one or more amino acid residues have been added with the proviso that said analogue either is insulino 25 tropic or is a prodrug of an insulinotropic compound . Examples of insulinotropic analogues of GLP-1 (1-37) are e.g. Met 8 -GLP-1 (7-37) wherein the alanine in position 8 has been replaced by methionine and the amino acid residues in position 1 to 6 have been deleted, and Arg 34 GLP-1 (7-37) wherein the valine in position 34 has been replaced with arginine and the amino acid residues in position 1 to 6 have been deleted. An example of an insulinotropic analogue 30 of exendin-4(1-39) is Ser 2 Asp 3 -exendin-4(1-39) wherein the amino acid residues in position 2 and 3 have been replaced with serine and aspartic acid, respectively (this particular ana logue also being known in the art as exendin-3). Insulinotropic derivatives of GLP-1 (1-37), exendin-4(1-39) and analogues thereof are what the person skilled in the art considers to be derivatives of these peptides, i.e. having at least one substituent which is not present in the 35 parent peptide molecule with the proviso that said derivative either is insulinotropic or is a WO 2007/006814 PCT/EP2006/064289 61 prodrug of an insulinotropic compound. Examples of substituents are amides, carbohydrates, alkyl groups and lipophilic substituents. Examples of insulinotropic derivatives of GLP-1 (1 37), exendin-4(1-39) and analogues thereof are GLP-1 (7-36)-amide, Arg 4 , Lys 26 (NE-(7 Glu(N"-hexadecanoyl)))-GLP-1 (7-37) and Tyr" -exendin-4(1-31)-amide. Further examples of 5 GLP-1 (1 -37), exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analogues thereof and insulinotropic derivatives thereof are described in WO 98/08871, WO 99/43706, US 5424286 and WO 00/09666. In another aspect of the present invention, the present compounds are administered in com bination with more than one of the above-mentioned compounds e.g. in combination with 10 metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc. 15 It should be understood that any suitable combination of the compounds according to the in vention with diet and/or exercise, one or more of the above-mentioned compounds and op tionally one or more other active substances are considered to be within the scope of the present invention. In one embodiment of the present invention, the pharmaceutical composi tion according to the present invention comprises e.g. a compound of the invention in combi 20 nation with metformin and a sulphonylurea such as glyburide; a compound of the invention in combination with a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovas tatin; etc. 25 PHARMACEUTICAL COMPOSITIONS The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceu 30 tically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Sci ence and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

WO 2007/006814 PCT/EP2006/064289 62 The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcuta neous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being 5 preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where ap 10 propriate, they can be prepared with coatings such as enteric coatings or they can be formu lated so as to provide controlled release of the active ingredient such as sustained or pro longed release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs. 15 Pharmaceutical compositions for parenteral administration include sterile aqueous and non aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile pow ders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot in jectable formulations are also contemplated as being within the scope of the present inven tion. 20 Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc. A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dos 25 ages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. The formulations may conveniently be presented in unit dosage form by methods known to 30 those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administra tion, typically doses are in the order of about half the dose employed for oral administration.

WO 2007/006814 PCT/EP2006/064289 63 The compounds of this invention are generally utilized as the free substance or as a pharma ceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds 5 of this invention which are generally prepared by reacting the free base with a suitable or ganic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When a compound according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compound accord 10 ing to the present invention contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be 15 useful in the preparation of compounds of the present invention and these form a further as pect of the present invention. For parenteral administration, solutions of the novel compounds of the formula (1) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first ren 20 dered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suit able for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution 25 and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or dilu ent may include any sustained release material known in the art, such as glyceryl mono 30 stearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the present invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

WO 2007/006814 PCT/EP2006/064289 64 Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally avail able formulations may be in the form of a powder or granules, a solution or suspension in an 5 aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to pro vide pharmaceutically elegant and palatable preparations. Tablets may contain the active 10 ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suit able for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium 15 stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorpo 20 rated herein by reference, to form osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phos phate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. 25 Aqueous suspensions may contain the active compounds in admixture with excipients suit able for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products 30 of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation prod ucts of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for 35 example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one WO 2007/006814 PCT/EP2006/064289 65 or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid 5 paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the 10 addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present. The pharmaceutical compositions of the present invention may also be in the form of oil-in 15 water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, natu rally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters de rived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and conden 20 sation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbi tan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propyl ene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preserva tive and flavoring and coloring agents. The pharmaceutical compositions may be in the form 25 of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be 30 employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this pur pose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compositions may also be in the form of suppositories for rectal administration of the 35 compounds of the present invention. These compositions can be prepared by mixing the WO 2007/006814 PCT/EP2006/064289 66 drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example. For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the 5 compounds of the present invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles. The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multi lamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as choles 10 terol, stearylamine, or phosphatidylcholines. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the pre sent invention. Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a 15 compound according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug therof, and one or more pharmaceutically acceptable carriers, excipients, or dilu ents. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. 20 The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gela tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical tablet that may be prepared by conventional tabletting techniques may contain: 25 Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite*1RP88* 1.0 mg 30 Magnesii stearas Ph. Eur. q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg 35 WO 2007/006814 PCT/EP2006/064289 67 * Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating. If desired, the pharmaceutical composition of the present invention may comprise a com 5 pound according to the present invention in combination with further active substances such as those described in the foregoing. The present invention also provides a method for the synthesis of compounds useful as in termediates in the preparation of compounds of formula (1) along with methods for the prepa ration of compounds of formula (1). The compounds can be prepared readily according to the 10 following reaction Schemes (in which all variables are as defined before, unless so specified) using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. PHARMACOLOGICAL METHODS 15 Glucokinase Activity Assay (1) Glucokinase activity is assayed spectrometrically coupled to glucose 6-phosphate dehydro genase to determine compound activation of glucokinase. The final assay contains 50 mM Hepes, pH 7.1, 50 mM KCI, 5 mM MgCl 2 , 2 mM dithiothreitol, 0.6 mM NADP, 1 mM ATP, 0.195 pM G-6-P dehydrogenase (from Roche, 127 671), 15 nM recombinant human glu 20 cokinase. The glucokinase is human liver glucokinase N-terminally truncated with an N terminal His-tag ((His) 8 -VEQILA......Q466) and is expressed in E.coli as a soluble protein with enzymatic activity comparable to liver extracted GK. The purification of His-tagged human glucokinase (hGK) was performed as follows: The cell pellet from 50 ml E. coli culture was resuspended in 5 ml extraction buffer A (25 mM HEPES, 25 pH 8.0, 1 mM MgCl 2 , 150 mM NaCl, 2 mM mercaptoethanol) with addition of 0.25 mg/ml ly sozyme and 50 pg/ml sodium azide. After 5 minutes at room temperature 5 ml of extraction buffer B (1.5 M NaCl, 100 mM CaCl 2 , 100 mM MgCl 2 , 0.02 mg/ml DNase 1, protease inhibitor tablet (Complete@ 1697498): 1 tablet pr. 20 ml buffer) was added. The extract was then cen trifugated at 15.000 g for 30 minutes. The resulting supernatant was loaded on a 1 ml Metal 30 Chelate Affinity Chromatography (MCAC) Column charged with Ni 2 ,. The column is washed with 2 volumes buffer A containing 20 mM imidazole and the bound his-tagged hGK is sub sequently eluted using a 20 minute gradient of 20 to 500 mM imididazol in buffer A. Fractions are examined using SDS-gel-electrophoresis, and fractions containing hGK (MW: 52 KDa) WO 2007/006814 PCT/EP2006/064289 68 are pooled. Finally a gelfiltration step is used for final polishing and buffer exhange. hGK con taining fractions are loaded onto a Superdex 75 (16/60) gelfiltration column and eluted with Buffer B (25 mM HEPES, pH 8.0, 1 mM MgCl 2 , 150 mM NaCl, 1 mM Dithiothreitol). The puri fied hGK is examined by SDS-gel electrophoresis and MALDI mass spectrometry and finally 5 20% glycerol is added before freezing. The yield from 50 ml E. coli culture is generally ap proximately 2-3 mg hGK with a purity >90%. The compound to be tested is added into the well in final 2.5% DMSO concentration in an amount sufficient to give a desired concentration of compound, for instance 1, 5, 10, 25 or 50 pM. The reaction starts after glucose is added to a final concentration of 2, 5, 10 or 15 mM. 10 The assay uses a 96-well UV plate and the final assay volume used is 200 pl/well. The plate is incubated at 250C for 5 min and kinetics is measured at 340 nm in SpectraMax every 30 seconds for 5 minutes. Results for each compound are expressed as the fold activation of the glucokinase activity compared to the activation of the glucokinase enzyme in an assay without compound after having been subtracted from a "blank", which is without glucokinase 15 enzyme and without compound. The compounds in each of the Examples exhibits activation of glucokinase in this assay. A compound, which at a concentration of at or below 30 pM gives 1.5 - fold higher glucokinase activity than the result from the assay without compound, is deemed to be an activator of glucokinase. 20 The glucose sensitivity of the compounds are measured at a compound concentration of 10 pM and at glucose concentrations of 5 and 15 mM. Glucokinase Activity Assay (II) Determination of glycogen deposition in isolated rat hepatocytes: 25 Hepatocytes are isolated from rats fed ad libitum by a two-step perfusion technique. Cell vi ability, assessed by trypan blue exclusion, is consistently greater than 80%. Cells are plated onto collagen-coated 96-well plates in basal medium (Medium 199 (5.5 mM glucose) sup plemented with 0.1 pM dexamethasone, 100 units/ml penicillin, 100 mg/ml streptomycin, 2 mM L-glutamine and 1 nM insulin) with 4 % FCS at a cell density of 30,000 cells/well. The 30 medium is replaced with basal medium 1 hour after initial plating in order to remove dead cells. Medium is changed after 24 hours to basal medium supplemented with 9.5 mM glu cose and 10 nM insulin to induce glycogen synthesis, and experiments are performed the next day. The hepatocytes are washed twice with prewarmed (37 0 C) buffer A (117.6 mM WO 2007/006814 PCT/EP2006/064289 69 NaCl, 5.4 mM KCI, 0.82 mM Mg 2

SO

4 , 1.5 mM KH 2

PO

4 , 20 mM HEPES, 9 mM NaHCO 3 , 0.1% w/v HSA, and 2.25 mM CaCl 2 , pH 7.4 at 370C) and incubated in 100 pl buffer A con taining 15 mM glucose and increasing concentrations of the test compound, such as for in stance 1, 5, 10, 25, 50 or 100 pM, for 180 minutes. Glycogen content is measured using 5 standard procedures(Agius, L.et al, Biochem J. 266, 91-102 (1990). A compound, which when used in this assay gives an significant increase in glycogen content compared to the result from the assay without compound, is deemed to have activity in this assay. Glucokinase Activity Assay (Ill) Stimulation of insulin secretion by glucokinase activators in INS-1 E cells 10 The glucose responsive p-cell line INS-1 E is cultivated as described by Asfari M et al., Endo crinology, 130, 167-178 (1992). The cells are then seeded into 96 well cell culture plates and grown to a density of approximately 5 x 104 per well. Stimulation of glucose dependent insu lin secretion is tested by incubation for 2 hours in Krebs Ringer Hepes buffer at glucose con centrations from 2.5 to 15 mM with or without addition of glucokinase activating compounds 15 in concentrations of for instance 1, 5, 10, 25, 50 or 100 pM, and the supernatants collected for measurements of insulin concentrations by ELISA (n= 4). A compound, which when used in this assay gives an significant increase in insulin secretion in response to glucose com pared to the result from the assay without compound, is deemed to have activity in this as say. 20 While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifica tions and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, effective dosages other than the preferred dosages as set 25 forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for glucokinase-deficiency mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations 30 or differences in the results are contemplated in accordance with the objects and practices of the present invention.

WO 2007/006814 PCT/EP2006/064289 70 EXAMPLES Abbreviations used in the Schemes and Examples are as follows: d = day(s) 5 g = gram(s) h = hour(s) MHz = mega hertz L = liter(s) M = molar 10 mg = milligram(s) min = minute(s) mL = milliliter(s) mM = millimolar mmol = millimole(s) 15 mol = mole(s) N = normal ppm = parts per million i.v. = intravenous m/z = mass to charge ratio 20 mp = melting point MS = mass spectrometry HPLC = high pressure liquid chromatography HPLC-MS = high pressure liquid chromatography - mass spectrometry NMR = nuclear magnetic resonance spectroscopy 25 p.o. = per oral Rt = retention time rt = room temperature s.c. = subcutaneous TLC = thin layer chromatography 30 BuOK = Potassium tert-butoxide Boc = tert-Butyloxcarbonyl CDI = carbonyldiimidazole DBU = 1,8-Diazabicyclo[5.4.0]-undec-7-en DCM (CH 2

CI

2 ) = dichloromethane, methylenechloride 35 DHOBt = 3,4-Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine WO 2007/006814 PCT/EP2006/064289 71 DIC = 1,3-Diisopropyl carbodiimide DCC = 1,3-Dicyclohexyl carbodiimide DIEA = NN-diisopropylethylamine DIPEA = NN-diisopropylethylamine 5 DMA = NN-dimethylacetamide DMAP = 4-(NN-dimethylamino)pyridine DMF = NN-dimethylformamide DMF = NN-dimethylformamide DMPU = N,N'-dimethylpropyleneurea, 1,3-dimethyl-2-oxohexahydropyrimidine 10 EDAC = 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride Et 2 0 = diethyl ether EtOAc = ethyl acetate HMPA = hexamethylphosphoric acid triamide HOBt = N-Hydroxybenzotriazole 15 HOAt = 7-Aza-1 -Hydroxybenzotriazole LAH, (LiAIH 4 ) = Lithiumaluminium hydride LDA = lithium diisopropylamide MeCN = acetonitrile MeOH = methanol 20 NMP = N-methylpyrrolidin-2-one NaH = Sodium Hydride

NH

2 OH = Hydoxylamine PyBroP = Bromotrispyrrolidinophosphonium hexafluorophosphate TEA (Et 3 N) = triethylamine 25 TFA = trifluoroacetic acid THF = tetrahydrofuran

CDCI

3 = deuterio chloroform

CD

3 OD = tetradeuterio methanol DMSO-d = hexadeuterio dimethylsu If oxide 30 HPLC-MS The RP-analysis was performed on an Agilent HPLC system (1100 degasser, 1100 pump, 1100 injector and a 1100 DAD) fitted with an Agilent MS detector system Model SL (MW 0 3000) and a S.E.D.E.R.E Model Sedex 75 ELS detector system using a Waters X-terra MS WO 2007/006814 PCT/EP2006/064289 72 C18 column (5 pm, 3.0 mm x 50 mm) with gradient elution, 5 % to 100 % solvent B (0.05 % TFA in acetonitrile) in solvent A (0.05 % TFA in water) within 6.75 min, 1.5 mL/min. Praparative HPLC 5 The RP-purification was performed on a Gilson system (3 Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquidhandler) using a Waters X-terra RP (10 pm, 30 mm x 150 mm) with gradient elution, 5 % to 95 % solvent B (0.05 % TFA in acetonitrile) in solvent A (0.05 % TFA in water) within 15 min, 40 mL/min, detection at 210 nm, temperature rt. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the 10 acetonitrile is removed, and then frozen and freeze dried. NMR Proton NMR spectra were recorded at ambient temperature using a Brucker Avance DPX 400 (400 MHz) with tetramethylsilane as an internal standard. Chemical shifts (5) are given 15 in ppm GENERAL The following examples and general procedures refer to intermediate compounds and final products for general formula (1) identified in the specification and in the synthesis schemes. 20 The preparation of the compounds of general formula (1) of the present invention is described in detail using the following examples. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The com pounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to 25 those skilled in the art, which is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the prepara tion of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may be prepared by a person skilled in the art in analogy with the 30 preparation of similar known compounds or by the General procedures A through K de scribed herein. The structures of the compounds are confirmed by either by nuclear magnetic resonance (NMR) and/or by HPLS-MS. 35 General procedure (A) WO 2007/006814 PCT/EP2006/064289 73 Compounds of the formula (Ia) according to the invention wherein R 1 , R 2 and A are as de fined for formula (1) can be prepared as outlined below: 1 0 RN H ACDI 1' I +R A N N A

H

2 N' H R 2 1|2 H R 5 (a) Step 1. The aminoheterocycle (NH 2 A) (Ill) wherein A is as defined for formula (1), can be converted using standard literature procedures (for example WO 2004/002481) to an acyl imidazonium intermediate with carbonyl diimidazole (CDI) or an equivalent of this in a solvent such as di 10 chloromethane, dichloroethane, tetrahydrofuran, or DMF. Treatment with R 1

R

2 NH (II), wherein R 1 and R 2 are as defined above, gives the compound of formula (Ia). The aminohet erocycle (NH 2 A) or secondary amine (R 1

R

2 NH) can be either commercially available com pounds or compounds that can be prepared following procedures described in the literature or prepared as described in the relevant example and general procedures. 15 Step 2. In some cases it might be more convenient to generate the final substituents on R 1 , R 2 and A after the urea formation. If in example the substituent on A in formula (Ia) contains an ester functionality this can be hydrolysed to the corresponding carboxylic acid using standard con 20 ditions for hydrolysis of esters. Suitable bases for the hydrolysis are NaOH and LiOH or equivalents of these in solvents like dioxane, THF, EtOH, MeOH and water or mixtures of these. The reactions can be performed at room temperature or at elevated temperatures. Other examples are described in general procedure I and J. 25 General procedure (B) 1 R SNaBH 3 CN R2 R2 WO 2007/006814 PCT/EP2006/064289 74 The desired amines R 1

R

2 NH described in General procedure (A) can in example be prepared by a reductive amination with a suitable primary amine and a ketone or an aldehyde. The re action can be performed in THF-MeOH or similar solvents in the presence of molecular 5 sieves (4A) or with 10% AcOH, using NaBH 3 CN or suitable equivalents of this as reducing agent. The primary amine, ketone and aldehyde can be either commercially available com pounds or compounds that can be prepared following procedures described in the literature or prepared as described in the relevant example and general procedures. General procedure (C) 10 ClBH1 NHR N H B R NH R O 2 RA O R (II) In case the primary amines (R 1

NH

2 ) are not sufficiently reactive to undergo reductive amina tion (general procedure B), the desired secondary amines can be prepared by initial forma tion of a secondary amide using a primary amine and an acid chloride or an equivalent 15 thereof and subsequent reduction of the amide. The amide reduction can be performed in THF or similar solvents using borane or suitable equivalents. The primary amine and the acid chloride can be either commercially available compounds or compounds that can be pre pared following procedures described in the literature or prepared as described in the rele vant example and general procedures. 20 General procedure (D) Preparation of trans-alkoxymethylcyclohexylamine and the like 1. ethylene glycol, O O 0 benzene 3. N F r-X, HCI (ac) 2. LiAIH4, ether 0 OMe OH OR OH

NH

2 NH,+ rCI sodium acetate Na C water/methanol EtCH OR OR OR OR Major isomer WO 2007/006814 PCT/EP2006/064289 75 The carbonyl group of 4-oxo-cyclohexanone carboxylic acid methyl ester can be protected as ketal by reaction with ethylene glycol in benzene with azepotropic removal of water. The es ter group can then be reduced with lithium aluminium hydride in a suitable solvent such as diethyl ether or tetrahydrofuran. The alcohol can be alkylated using sodium hydride and a 5 suitable alkyl halide (R-X, wherein R is an appropiate radical defined according to the inven tion) in a solvent such as tetrahydrofuran or DMF. Ketal deprotection of the product under standard acidic conditions gives the corresponding ketone, which can be converted to the corresponding oxime upon treatment with hydroxylamine and a suitable base (for example sodium acetate). Reduction of the oxime using sodium in ethanol affords the trans-4 10 alkoxymethyl-cyclohexylamine as the major isomer, which, if necessary can be purified by recrystallisation of the corresponding HCI salt. General Procedure (E) Preparation of trans-4-alkoxy-cyclohexylamine and the like R R HO, base 0 NH 2

NH

2 5 H O,, alk acting agent N H I INH2 2-(trans-4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (Glennon et al. J. Med. Chem. 1996, 39, 1, 314-322) can be alkylated with an alkylating agent such as R-halides (wherein R is a radi cal defined according to the invention) or an equivalent of this using a base such as NaH, potassium tert-butoxid, DBU or the like in a solvent like DMF, NMP, DMSO, THF at tempera 20 tures from -10 to 120 *C. Deprotection of the trans-4-alkoxy-cyclohexyl-isoindole-1,3-dione can be achieve using hydrazine in ethanol at room temperature or at elevated temperatures. General Procedure (F) Preparation of trans-4-alkyl-cyclohexylamines and the like 25 O N lHlH 2 NH+ NH NH 3

+

HONH3+ cI Na CIH CI NaQAc EtOH K> R H,0/MeOH R R R Major isomer A 4-substituted cyclohexanone (wherein R is a radical defined according to the invention) can be converted to the corresponding oxime upon treatment with hydroxylamine hydrochlo- WO 2007/006814 PCT/EP2006/064289 76 ride and a suitable base such as sodium acetate in a solvent mixture such as water/MeOH at elevated temperature. Reduction of the oxime using sodium in ethanol at elevated tempera tures affords the trans-4-alkyl/aryl-cyclohexylamine as the major isomer, which, if necessary can be purified by recrystallisation of the corresponding HCI salt. 5 General Procedure (G) Preparation of alkyl-(trans-4-alkyl-cyclohexyl)-amine and the like 10 UH3+ HN'R ~ CI base R KI R x = CI, Br R To a mixture of a 4-trans-substituted cyclohexylamine (wherein R is a radical defined accord ing to the invention), hydrochloride in DMF, NMP, MeCN or a similar solvent was added po tassium carbonate, NaOH or an equivalent of such a base. The alkyl halide (wherein R 1 is 15 defined according to the invention) was added and the reaction mixture was heated until completion of the reaction. The crude product can be used as such for subsequent reactions or alternatively it can be purified before further reactions. General Procedure (H) 20 Preparation of 2-Amino-thiazole-5-sulfonic acid amides 0 N O NN S + HN,R NN-R' SN-R' H 0 base S EtOH H2 0 R' 0 0 A mixture of an amine, protected amino acid or the like (wherein R and R' are radicals de 25 fined according to the invention) is reacted with 2-acetylamino-thiazole-5-sulfonyl chloride prepared as described in J. Am. Chem. Soc, 1947, 69, 2063) in the precence of a base such as DIPEA in DCM. N-Deacetylation of the intermediate can be achieved upon heating in the presence of HCI in dioxane/EtOH to give the required sulfonamido-2-aminothiazole.

WO 2007/006814 PCT/EP2006/064289 77 General procedure (1) R1' N N \ R R1 ,, R H oxidizing agent N s O o H 5 5-Thiosubstituted aminothiazole-urea derivatives can be oxidized with an oxidizing agent such as m-chloroperbenzoic acid in DCM, with oxone and montmorillonite in water/DCM or with hydrogenperoxide in AcOH (J. Org. Chem. 1965, 2688-2691) to give the corresponding sulfonyl derivatives. 10 General procedure (J) 1) NaBH 4 N 0DIPEA Br OH 2)AcCI H 2 N S EtOH R1 R, NOH 00 H 3-(2-Amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester can be prepared from 15 5-thiocyanato-thiazol-2-ylamine by treatment with sodium borohydride in MeOH followed by addition of 3-bromo-2,2-dimethyl-propionic acid. After aquous work up the intermediate acid can be treated with HCI in EtOH to give the 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl propionic acid ethyl ester. The aminothiazole ester can be coupled to the final urea derivative following the general pro 20 cedure (A). General procedure (K) WO 2007/006814 PCT/EP2006/064289 78 0 H O , O MsOH m HO, N 0 DPE MSON _11 D DIPEA ~ (X N 01 = ' DCM

K

2

CO

3 n = 1,2 acetone 0 N 0 H () - TFA/DCM m n =1,2=1,2 M =0,1 m = 0,1 The hydroxypropyl- and hydroxyethylderivatives, prepared as described in the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] th iazol-5-ylsu Ifanyll-acetic acid and {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl) 5 ureido]-thiazol-5-ylsulfanyl}-acetic acid, can be treated with mesyl chloride and DIPEA in DCM to obtain the corresponding mesylate. This can be treated with a thiol like thiophenol og phenyl-methanethiol in acetone using potassium carbonate as base. After removal of the Boc group the secondary amine can be coupled and hydrolysed using the methods described in general procedure (A) to give the final urea thiazole. 10 Example 1 [2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid 15 (General procedure (A) and (B)) N s H OH WO 2007/006814 PCT/EP2006/064289 79 (Reductive amination: Preparation of cyclohexyl phenetylamine. Phenethylamine (121 mg, 1.0 mmol) in a 2:1 mixture of THF-MeOH (2 mL) was added cyclo hexanone (98 mg, 1.0 mmol) and molecular sieves (4A, 80 mg). The reaction mixture was 5 shaken for 1 h before NaBH 3 CN (126 mg, 2.0 mmol) was added. The reaction mixture was shaken for 24 h before it was filtered and the filtrate was concentrated in vacuo to give the intermediate cyclohexyl phenetylamine. Coupling: 10 Preparation of: (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester 5-Bromo-2-aminothiazole (25 g, 96 mmol) and K 2

CO

3 (26.5 g, 192 mmol) was suspended in DMF (50 mL) and stirred to 0 0C. Ethyl thioglycolate (11.6 mL, 96 mmol) was added during 10 min. The reaction mixture was allowed to reach room temperature and stirred for further 16 h. Addition of water (100 mL) and EtOAc (150 mL). Separation of the organic phase fol 15 lowed by extraction of the aqueous phase with EtOAc (2x1 00 mL).The combined organic phases were washed with aqueous NaHCO3 (2000 mL), brine (2x200 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromathography (ISCO 330 g silica column, eluent A: heptane / B: 2% TEA in EtOAc. Gradient from 30% B ->100% B.) to give 50-65% pure (2-aminothiazol 20 5-ylsulfanyl) acetic acid ethyl ester as a dark red-brown oil. 1 H NMR (CDCI 3 ): 57.16 (s, 1H), 5.45 (bs, 2H), 4.26 (q, 2H), 3.39 (s, 2H), 1.28 (t, 3H). 2-Amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (218 mg, 1.0 mmol) in DCM (2 mL) was added in sequence CDI (162 mg, 1.0 mmol), DMAP (6 mg, 0.05 mmol) and DIPEA (129 mg, 25 1.0 mmol) and the mixture was stirred for 1 h before it was added to the intermediate cyclohexyl phenethylamine. The reaction mixture was stirred for 16 h before the volatiles were removed in vacuo. Hydrolysis: 30 MeOH (1 mL) was added followed by NaOH (0.50 mL 10 N, 5 mmol) and shaken for 16 h before the mixture was quenced with AcOH (0.286 mL, 5 mmol), whereupon MeOH (0,5 mL) and DMSO (0,5 mL) was added. The mixture was purified on preparative HPLC to give 120 mg (29%) of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid.

WO 2007/006814 PCT/EP2006/064289 80 'H NMR (400 MHz, DMSO-d 6 ) 8 7.42 (s, 1 H), 7.35-7.25 (m, 4H), 7.24-7.19 (m, 1 H), 4.10-3.95 (m, 1 H), 3.5 (s, 2H), 3.45-3.35 (m, 2H), 2.85-2.75 (m, 2H), 1.80-1.70 (m, 2H), 1.65-1.40 (m, 5H), 1.40-1.25 (m, 2H), 1.18-1.05 (m, 1 H). HPLC-MS : m/z = 420 (M+1), Rt = 2.1 min 5 Example 2 [2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid

CH

3 OH N N S H 10 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.42 (s, 1H), 4.02-3.90 (m, 1H), 3.49 (s, 2H), 3.25-3.15 (m, 2H), 1.8-1.0 (m, 14H), 0.89 (t, 3H). 15 HPLC-MS: m/z = 372, Rt= 2.0 min Example 3 {2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

CH

3 OH

H

3 C N0N<S 20 H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from 3-methyl-butylamine, cyclohexanone and 2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 4.02-3.90 (m, 1H), 3.49 (s, 2H), 3.28-3.18 (m, 25 2H), 1.80-1.00 (m, 13H), 0.90 (d, 6H). HPLC-MS : m/z = 386, Rt= 2.1 min WO 2007/006814 PCT/EP2006/064289 81 Example 4 {2-[3-Cyclohexyl-3-(2,2-dimethyl-propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid

CH

3 H 3C CHO N N N S OH 5 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from 3,3-dimethyl-propylamine, cyclohexanone and 2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 3.49 (s, 2H), 3.19 (s, 2H), 2.08-1.85 (m, 2H), 10 1.80-1.62 (m, 4H), 1.61-1.52 (m, 1 H), 1.30-1.00 (m, 3H), 0.91 (s, 9H). HPLC-MS : m/z = 386, Rt= 2.1 min Example 5 {2-[3-(2-Cyclohex-1-enyl-ethyl)-3-cyclohexyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid 15 N s O OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from 2-(1 -cyclohexenyl)-ethylamine, cyclohexanone and 2-amino th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 20 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 4.42 (bs, 1 H), 4.0-3.9 (m, 1 H), 3.48 (s, 2H), 3.38-3.22 (m, 2H), 2.15-2.05 (m, 2H), 2.0-1.9 (m, 4H), 1.80-1.00 (m, 12H) HPLC-MS: m/z= 424, Rt= 2.3 min Example 6 25 [2-(3-Bicyclo[2.2.1 ]hept-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid WO 2007/006814 PCT/EP2006/064289 82 N N O H OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from c-bicyclo[2.2.1]hept-2-yl-methylamine, cyclohexanone and 2 amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 3.9-3.7 (m, 1 H), 3.49 (s, 2H), 3.40-3.25 (d, 2H), 2.20-1.95 (m, 3H), 1.80-0.70 (m, 20H). HPLC-MS: m/z= 424, Rt= 2.3 min Example 7 10 [2-(3-Bicyclo[2.2.1 ]hept-5-en-2-ylmethyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl] acetic acid N N S O H OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 15 ylsulfanyl]-acetic acid, from c-bicyclo[2.2.1]hept-5-en-2-yl-methylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) (mixture of two isomers) 8 7.40 (s, 1 H), 6.24-6.19 (m, 0.7H), 6.10-6.03 (m, 1.3H), 3.95-3.70 (m, 1H), 3.48 (s, 2H), 3.10-2.88 (m, 2H), 2.80-2.70 (m, 2H), 2.35-2.25 (m, 1 H), 1.87-1.00 (m, 11.3H), 0.65-0.55 (m, 0.7H) 20 HPLC-MS: m/z= 422, Rt= 2.2 min Example 8 {2-[3-Cyclohexyl-3-(2-cyclohexyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid WO 2007/006814 PCT/EP2006/064289 83 N N O OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 2-cyclohexylehylamine, cyclohexanone and 2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 5 HPLC-MS : m/z = 426 Rt= 2.4 min Example 9 3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid 0 C 0 /_ OH N N S 10 H Preparation of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester: 5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K 2

CO

3 (26.5 g, 192 mmol) and the mixture was purged with N 2 for 5 min. The mixture was cooled to 00C on an ice bath before 3-mercaptopropionic acid ethyl ester (12.9 g, 96 mmol) was added dropwise 15 over the course of 30 min. The reaction mixture was stirred for 16 hours before water (400 mL) was added. The aquous mixture was extracted with Et 2 0 (1 x 500 mL, 2 x 250 mL). The combined organic phases was washed with saturated NH 4 CI (3 x 150 mL), dried (MgSO4). The solvent was removed in vacuo to give a dark residue which was purified by column chromatography (SiO 2 , EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 20 g (49%) of the desired compound. 'H NMR (400 MHz, CDC1 3 ) 8 7.1 (s, 1 H), 5.2 (bs, 2H), 4.2 (q, 2H), 2.8 (t, 2H), 2.6 (t, 2H), 1.3 (t, 3H). 3-[2-(3-Cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid was prepared as 25 described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-phenethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 84 'H NMR (400 MHz, DMSO-d 6 ) 8 7.41 (s, 1H), 7.45-7.15 (m, 5H), 4.10-3.95 (m, 1H), 3.50-3.40 (m, 2H), 2.87 (t, 2H), 2.78 (m, 2H), 2.5 (t, 2H), 1.8-1.0 (m, 10 H) HPLC-MS : m/z = 386, Rt= 2.1 min 5 Example 10 3-[2-(3-Butyl-3-cyclohexyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid OHOH O N N N S H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 10 ylsu Ifanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d 6 ) 8 7.40 (s, 1 H), 4.05-3.90 (m, 1 H), 3.2 (t, 2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.80-1.00 (m, 14H), 0.89 (t, 3H) HPLC-MS: m/z= 434, Rt= 2.2 min 15 Example 11 3-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid CH 0

H

3 C N N N S H 20 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from 3-methylbutylamine, cyclohexanone and 2-amino-thiazol-5 ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d 6 ) 8 7.40 (s, 1 H), 4.04-3.92 (m, 1 H), 3.28-3.18 (m, 2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.80-1.00 (m, 13H), 0.90 (d, 6H) 25 HPLC-MS: m/z= 400, Rt= 2.2 min Example 12 WO 2007/006814 PCT/EP2006/064289 85 3-{2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-th iazol-5-ylsulfanyl}-propionic acid 'N OH N N S H

CH

3 5 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from phenyl acetaldehyde, trans-4-methylcyclohexylamine hydrochlo ride (prepared via the methode described in J. Med. Chem. 1971, vol 14, p. 610) and 2 amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 10 'H NMR (400 MHz, DMSO-d 6 ) 8 7.42 (s, 1 H), 7.35-7.25 (m, 5H), 4.08-3.92 (m, 1 H), 3.50-3.35 (m, 2H), 2.87 (t, 2H), 2.82-2.72 (m, 2H), 1.80-0.95 (m, 9H), 0.88 (d, 3H). HPLC-MS: m/z= 448, Rt= 2.3 min Example 13 15 3-{2-[3-Butyl-3-( trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-propionic acid CH 0 O N /_ OH 'N N I, H

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from butyraldehyde, trans-4-methylcyclohexylamine hydrochloride and 20 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 'H NMR (400 MHz, DMSO-d 6 ) 8 7.40 (s, 1 H), 4.02-3.90 (m, 2H), 3.25-3.15 (m, 2H), 2.83 (t, 2H), 2.50 (t, 2H), 1.75-0.95 (m, 13H), 0.92-0.82 (m, 6H) HPLC-MS: m/z= 400, Rt= 2.3 min 25 WO 2007/006814 PCT/EP2006/064289 86 Example 14 3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll propionic acid

CH

3 0 ,OH

H

3 C OH N N S 5

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from isovaleraldehyde, trans-4-methylcyclohexylamine hydrochloride and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 10 'H NMR (400 MHz, CDC1 3 ) 8 11.2 (bs, 1H), 7.28 (s, 1H), 3.25 (m, 2H), 3.00 (m, 2H), 2.75 (m, 2H), 2.00-1.00 (m, 13H), 0.95-0.87 (m, 9H). HPLC-MS: m/z= 414, Rt= 2.4 min Example 15 15 3-{2-[3-(2-Cyclohex-1 -enyl-ethyl)-3-cyclohexyl-ureido]-th iazol-5-ylsu Ifanyl}-propionic acid 0 HOH N N S 6H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 20 ylsulfanyl]-acetic acid, from 2-(1 -cyclohexenyl)ethylamine hydrochloride, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. HPLC-MS: m/z= 439, Rt= 2.5 min 25 Example 16 {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 87

CH

3 OH N N S H

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, isovaleraldehyde 5 and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 4.00-3.95 (m, 1H), 3.48 (s, 2H), 3.25-3.18 (m, 2H), 1.73-1.65 (m, 2H), 1.65-1.44 (m, 5H), 1.40-1.25 (m, 3H), 1.14-1.00 (m, 2H), 0.92-0.84 (m, 9H). 10 HPLC-MS: m/z= 435, Rt= 2.3 min Example 17 {2-[3-(trans-4-Methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid OH N N S H 15 CH 3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, phenylacetalde hyde and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 20 'H NMR (400 MHz, DMSO-d) 8 12 (bs, 1H), 7.42 (s, 1H), 7.35-7.25 (m, 4H), 7.23-7.18 (m, 1 H), 4.05-3.95 (m, 1 H), 3.50 (s, 2H), 3.45-3.35 (m, 2H), 2.82-2.75 (m, 2H), 1.72-1.65 (m, 2H), 1.62-1.50 (m, 4H), 1.40-1.30 (1H), 1.12-1.00 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 400, Rt= 2.3 min 25 Example 18 WO 2007/006814 PCT/EP2006/064289 88 {2-[3-(2-Cyclohex-1 -enyl-ethyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid OH N N s O -H

CH

3 5 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, cyclohexen-1 -yl acetaldehyde (Prepared according to the procedure given in Oppolzer, W. et al. Tetrahedron, 1985, 41, 17, 3497-3509) and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hy drochloride was added one equivalent DIPEA prior to the reaction. 10 'H NMR (400 MHz, DMSO-d) 8 12.5 (bs, 1H), 7.40 (s, 1H), 5.42 (s, 1H), 3.48 (s, 2H), 2.12 2.05 (m, 2H), 1.98-1.92 (m, 4H), 1.72-1.65 (m, 2H), 1.64-1.45 (m, 9H), 1.40-1.25 (m, 2H), 1.15-1.00 (m, 2H), 0.88 (d, 3H). HPLC-MS: m/z= 438, Rt= 2.4 min 15 Example 19 {2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid

CH

3

H

3 C N s O H OH

CH

3 20 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2 enal and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.

WO 2007/006814 PCT/EP2006/064289 89 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1 H), 5.12-5.05 (m, 1 H), 4.15-3.95 (m, 1 H), 3.92 (d, 2H), 3.32 (s, 2H), 1.80-1.70 (m, 3H), 1.70 (s, 6H), 1.55-1.42 (m, 2H), 1.40-1.24 (m, 2H), 1.20-1.05 (m, 2H), 0.90 (d, 3H). HPLC-MS : m/z = 398, Rt= 2.1 min 5 Example 20 3-{2-[3-(3-Methyl-but-2-enyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll propionic acid

CH

3

H

3 C O HO 10 CH3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2 enal and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction. 15 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1H), 5.15-5.05 (m, 1H), 3.92 (d, 2H), 3.05-2.95 (m, 2H), 2.75-2.68 (t, 2H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.70 (s, 3H), 1.68 (s, 3H)1.60-1.40 (m, 3H), 1.40-1.20 (m, 3H), 0.91 (d, 3H). HPLC-MS: m/z= 412, Rt= 2.2 min 20 Example 21 {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid (General procedure (F), (G), (B) and (A, step 2))

CH

3 0N S OH H 0 25

H

3 C CH 3 WO 2007/006814 PCT/EP2006/064289 90 Preparation of trans-4-alkyl-cyclohexylamines: Sodium (45 g, 1.96 mol) was slowly added to a solution of 4-ethylcyclohexanone oxime (33 g, 0.23 mol) (prepared according to lift. R.O.Hutchins et al. J.Org. Chem. 60 (1995) 7396 7405)) in 99.9 % ethanol (500 mL) while keeping the temperature below 65 0C. The reaction 5 mixture was heated at reflux temperature for 11/2 h and then stirred at room temperature for further 16 h. A mixture of water (500 mL) and ethanol (100 mL) was added and the mixture was extracted with diethyl ether (3 x 250 mL). The combined organic phases was washed with brine (150 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (100 mL), pH was adjusted to approx. 3 with 4 N hy 10 drochloric acid (60 mL) and the solution was evaporated to dryness in vacuo to give crude ethylcyclohexylamine. The product was purified by recrystallization from ethanol/acetonitrile (4:1) to give 4-trans-ethylcyclohexylamine, hydrochloride as white crystalls. Preparation of alkyl-(trans-4-alkyl-cyclohexyl)-amine: 15 To a mixture of 4-trans-ethylcyclohexylamine, hydrochloride (1.5 g, 9.2 mmol), dry DMF (40 mL), and potassium carbonate (3.75 g, 27.2 mmol) was added 1 -bromo-3-methylbutane (1.125 mL, 9.4 mmol). The mixture was heated at 55 0C for 24 h, filtered, and evaporated to dryness in vacuo after adjusting the pH to 3-4 by adding hydrogen chloride in diethyl ether. The crude product of (4-trans-ethylcyclohexyl)-(3-methylbutyl)-amine, hydrochloride was 20 used in the next step without further purification. Coupling: To a solution of (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (200 mg, 0.92 mmol) in dry THF (2 mL) was added CDI (152 mg, 0.92 mmol) and DMAP (50 mg, 0.046 mmol). The 25 mixture was stirred at room temperature for 11/2 h after which 4-trans-ethylcyclohexylamine, hydrochloride (220 mg, 0.94 mmol) in THF (3 mL) and DIPEA (0.83 mL, 4.77 mmol) were added. Stirring was continued overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and purified on silica gel (gradient, from heptane:ethyl ace tate (9:1) to heptane:ethyl acetate (4:6)) to give 86 mg (yield: 21 %) of ethyl {2-[3-(4-trans 30 ethylcyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetate. Hydrolysis: To a solution of ethyl {2-[3-(4-trans-ethylcyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetate (86 mg, 0.195 mmol) in dioxan (1 mL) was added 1 N sodium hydroxide 35 (0.75 mL). The mixture was stirred for 4 h at room temperature. 2 N hydrochloric acid (0.38 WO 2007/006814 PCT/EP2006/064289 91 mL) was added and the mixture was evaporated partly in vacuo to remove dioxan The resi due was stirred with water and dried in vacuo to give the title compound as white crystals 'H NMR (400 MHz, CDC1 3 ) 8 7.26 (s, 1 H), 3.33 (s, 2H), 3.29-3.20 (m, 2H), 1.85-1.75 (m, 4H), 1.70-1.60 (m, 1 H), 1.55-1.40 (m, 4H), 1.30-1.20 (m, 3H), 1.18-1.05 (m, 3H), 0.93 (d, 6H), 5 0.89 (t, 3H) HPLC-MS: m/z = 415, Rt= 2.4 min Example 22 {2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid CH, 0N s OH H 0 10 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 phenethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.32-7.20 (m, 6H), 3.51 (m, 2H), 3.32 (s, 2H), 2.90 (m, 2H), 15 1.83 (m, 4H), 1.57-1.49 (m, 2H), 1.25 (m, 3H), 1.12 (m, 3H), 0.89 (t, 3H HPLC-MS: m/z = 448, Rt= 2.4 min Example 23 {2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 20 acetic acid

CH

3 0N1 OH H O Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 cyclohexylethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 92 'H NMR (400 MHz, CDC1 3 ) 8 7.26 (s, 1 H), 3.32 (s, 2H), 3.28 (m, 2H), 1.84-1.64 (m, 1 OH), 1.47 (m, 4H), 1.34 (m, 1 H), 1.25-1.10 (m, 9H), 0.95 (m, 2H), 0.89 (t, 3H); HPLC-MS: m/z = 455, Rt= 2.7 min 5 Example 24 3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl} propionic acid CHO N S H

H

3 C CH 3 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) 10 u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 1 bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1H), 3.22 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.86 (m, 4H), 1.61 (m, 2H), 1.45 (m, 4H), 1.25 (m, 4H), 1.12 (m, 2H), 0.97-0.89 (m, 9H). HPLC-MS: m/z = 429, Rt= 2.5 min 15 Example 25 3-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-th iazol-5-ylsu Ifanyl}-propionic acid 0 0 H 20 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 phenethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.27-7.18 (m, 6H), 3.43 (broad s, 2H), 2.87 (m, 4H), 2.72 (m, 2H), 1.89 (m, 4H), 1.52-1.43 (m, 2H), 1.26-1.09 (m, 5H), 0.88 (m, 3H). 25 HPLC-MS: m/z = 463, Rt= 2.5 min Example 26 WO 2007/006814 PCT/EP2006/064289 93 3-{2-[3-(2-Cyclohexyl-ethyl)-3-(4-trans-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} propionic acid CH, N N OH (:N N H Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) 5 u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 cyclohexylethyl bromide and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1 H), 3.23 (m, 2H), 2.98 (m, 2H), 2.73 (m, 2H), 1.86 (m, 4H), 1.74-1.64 (m, 6H), 1.50-1.42 (m, 4H), 1.28-1.10 (m, 10H), 0.98-0.86 (m, 6H) HPLC-MS: m/z = 469, Rt= 2.8 min 10 Example 27 2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2 methyl-propionic acid CH, LN H3 CH3OH H 0 HC CH, 15 Preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester: 2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol) in MeOH (400 mL) was stirred at -10 C. Bromine (18.0 mL, 350 mmol) dissolved in MeOH (100 mL) satu rated with with NaBr was slowly added keeping the internal temperature between -10 and 0 20 C. After the addition the mixture was stirred at 0 0C for 3 h and the reaction mixture was poured into ice water (1500 mL). Aqueous NH 4 0H was added to pH ca 8.5 causing precipita tion of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55%) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals. 25 Step 2: In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol) dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane (DTT, 9.8 g, 64 mmol) and WO 2007/006814 PCT/EP2006/064289 94 stirred at room temperature for 11/2 h. Then 2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K 2

CO

3 (10.5 g, 76 mmol) was added and the reaction mixture was stirred for further 16 h. Addition of water (500 mL) and EtOAc (500 mL). Separation of the organic phase followed by extraction of the aqueous phase with EtOAc (2x300 mL). The combined 5 organic phases were washed with water (500 mL) and brine (2x400 mL) and dried (MgSO4), filtered and evaporated.' The crude product was dissolved in a small amount of DCM and purified by flash chromathography (heptane/EtOAc 2:1 -> 1:2). Fractions containing the product were pooled and evaporated to a product (ca 14 g) containing impurities of DDT. The crude product was dissolved in diethyl ether (100 mL) and washed with water eight times. 10 The ether phase was dried (MgSO4), filtered and evaporated to give 8.45 g (54%) of 95% pure 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester as light brown crys tals. 2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl 15 propionic acid was prepared as described for the synthesis of {2-[3-(4-trans-ethyl cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid, from 4-trans-ethyl cyclohexylamine hydrochloride, 1 -bromo-3-methylbutane and 2-(2-amino-thiazol-5 ylsulfanyl)-2-methyl-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.05 (s, 1 H), 3.31 (m, 2H), 1.85 (m, 4H), 1.67 (m, 2H), 1.59 (s, 20 6H), 1.51 (m, 4H), 1.23 (m, 3H), 1.12 (m, 3H), 0.94 (d, 6H), 0.89 (t, 3H) HPLC-MS: m/z = 442, Rt= 2.5 min Example 28 2-{2-[3-(4-trans-Ethyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-2-methyl 25 propionic acid CH O ' N O H S As the DTT impurities is not easily removed by flash chromathography it's recommended that the crude product is dissolved in Et20 and subsequently washed with water several times at then purified by flash chromathography.

WO 2007/006814 PCT/EP2006/064289 95 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 phenethyl bromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.31-7.21 (m, 5H), 7.07 (s, 1 H), 3.54 (bs, 2H), 2.94 (m, 2H), 5 1.87 (m, 4H), 1.59 (s, 6H), 1.54 (m, 2H), 1.25-1.20 (m, 4H), 1.13 (broad m, 2H), 0.89 (t, 3H) HPLC-MS: m/z = 477, Rt= 2.6 min Example 29 {2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylaminol 10 acetic acid (General procedure (H) (B) and (A step 2)) N S 0OH

H

3 C

CH

3 Preparation of 2-Amino-thiazole-5-sulfonic acid amides: 15 Step 1. A mixture of glycine ethylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5 sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1 N HCI to pH 2 resulted in precipitation. The precipitate was isolated by filtration, washed with water and dried to give (2-acetylamino-thiazole-5-sulfonylamino)-acetic acid 20 ethyl ester (64%) as crystals. This was suspended in EtOH (15 mL) and added 4N HCI in di oxane (15 mL) and heated for 4 h at 80 0C and then cooled to room temperature. Addition of aqueous NaHCO3 to neutral pH. The organic phase was isolated and the aqueous phase was extracted with CH 2 Cl 2 , and the combined organic phases were dried and concentrated in vacuo to give (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (80%) as colourless 25 crystals. Coupling: An equimolar mixture of 1,1 -carbonyldiimidazole, (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester and DMAP (5mol%) in THF was heated for 5 h at 50-60 0C and then cooled 30 to room temperature. Then (3-methyl-butyl)-(4-methyl-cyclohexyl)-amine (1 equivalent; pre pared following the procedure described in the preparation of [2-(3-cyclohexyl-3-phenethyl ureido)-thiazol-5-ylsulfanyl]-acetic acid) was added and the reaction is stirred overnight at WO 2007/006814 PCT/EP2006/064289 96 room temperature. The reaction mixture was quenched with water. The organic phase was isolated and the aqueous phase was extracted with CH 2 Cl 2 , and the combined organic phases were dried and concentrated in vacuo. The crude product was dissolved in MeCN and purified using HPLC to give {2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido] 5 thiazole-5-sulfonylamino}-acetic acid ethyl ester as crystals. Hydrolysis: {2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylaminol-acetic acid ethyl ester was dissolved in MeOH and treated with 15 equivalents of 1 N NaOH for 2 10 days at room temperature. MeOH was removed by evaporation. Addition of 1 N HCI to pH<1 caused precipitation. The precipitate was isolated by filtration, washed with water and dried to give {2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylaminol-acetic acid as crystals. 'H NMR (400 MHz, CDC1 3 +2 dr DMSO) 8 7.80 (s, 1 H), 6.68 (br t, 1 H), 4.00 (br s, 1 H), 3.74 15 (d, 2H), 3.29-3.23 (m, 2H), 1.80-1.08 (m, 12H), 0.95 (d, 6H), 0.91 (d,3H). HPLC-MS: m/z = 447, Rt= 2.13 min Example 30 3-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 20 sulfonylamino}-propionic acid

H

3 C,, C H S 0

'

0 OH

H

3 C

CH

3 Prepared as described for the preparation of {2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl) ureido]-thiazole-5-sulfonylamino}-acetic acid using the appropriate amino ester in Step 1. 'H NMR (400 MHz, CDC1 3 +2dr DMSO) 8 7.80 (s, 1 H), 6.38 (br t, 1 H), 3.99 (br s, 1 H), 3.28 25 3.21 (m, 4H), 2.55 (t, 2H), 1.80-1.07 (m, 12H), 0.97 (d, 6H), 0.92 (d,3H). HPLC-MS: m/z = 461, Rt= 2.13 min Example 31 (Methyl-{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5 30 sulfonyl}-amino)-acetic acid WO 2007/006814 PCT/EP2006/064289 97 H3C,, OH N S "

H

3 C

CH

3 Prepared as described for the preparation of {2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl) ureido]-thiazole-5-sulfonylamino}-acetic acid using the appropriate amino ester in Step 1. 'H NMR (400 MHz, DMSO) 8 7.89 (s, 1 H), 3.97 (br t, 1 H), 3.88 (s, 2H), 3.26 (br t, 2H), 2.82 5 (s, 3H), 1.73-1.01 (m, 12H), 0.90 (d, 6H), 0.88 (d, 3H). HPLC-MS: m/z = 461, Rt= 2.24 min Example 32 (S)-1-{2-[3-(3-Methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyll 10 pyrrolidine-2-carboxylic acid

H

3 C,, <K N H ok OH 0

H

3 C

CH

3 Prepared as described for the preparation of {2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl) ureido]-thiazole-5-sulfonylamino}-acetic acid using the appropriate amino ester in Step 1. 'H NMR (400 MHz, DMSO) 8 12.75 (br s, 1H), 11.4 (br s, 1H), 7.93 (s, 1H), 4.02 (dd, 1H), 15 3.97 (br t, 1H), 3.45-3.39 (m, 1H), 3.27-3.18 (m, 3H), 2.05-1.02 (m, 16H), 0.90 (d, 6H), 0.88 (d,3H). HPLC-MS: m/z = 487, Rt= 2.27 min Example 33 20 {2-[3-(4-trans-tert-Butyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid CH H 3 C0 H C O H N sS H O

H

3 C CH 3 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-tert-butyl-cyclohexylamine WO 2007/006814 PCT/EP2006/064289 98 hydrochloride, 1 -bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester 'H NMR (400 MHz, CDC1 3 ) 8 7.26 (s, 1 H), 3.95 (bs, 1 H), 3.32( s 2H), 3.27(m, 2H), 1.84 (m, 4H), 1.65 (m, 1 H), 1.48 (m, 4H), 1.25 (m, 2H), 0.98 (m, 1 H), 0.94 (d, 6H), 0.87 (s, 9H). 5 HPLC-MS: m/z = 442, Rt= 2.5 min Example 34 {2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid N N1s OH 10 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-isopropyl-cyclohexylamine hydrochlo ride, 1 -bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester 'H NMR (400 MHz, CDC1 3 ) 8 7.22 (s, 1 H), 4.02 (broad s, 1 H), 3.31( s 2H), 3.27(m, 2H), 1.81 15 (m, 4H), 1.66 (m, 1 H), 1.53-1.43 (m, 5H), 1.23 (m, 2H), 1.05 (m, 1 H), 0.94 (d, 6H), 0.88 (d, 6H). HPLC-MS: m/z = 428, Rt= 2.5 min Example 35 20 3-{2-[3-(4- trans-tert-B utyl-cyclohexyl)-3-(3-methyl-butyl)-u re ido]-th iazol-5-ylsulfanyl} propionic acid

H

3 C

CH

3 N 0OH HC 0 HG CH 3 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) 25 u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-tert-butyl-cyclohexylamine hydrochlo ride, 1 -bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1 H), 3.65 (broad s, 1 H), 3.21 (m, 2H), 2.99 (broad m, 2H), 2.72 (m, 2H), 1.88 (m, 4H), 1.62 (m, 1 H), 1.44 (m, 3H), 1.31 (m, 1 H), 0.98 (m, 2H), 0.93 (d, 6H), 0.89 (s, 9H) WO 2007/006814 PCT/EP2006/064289 99 HPLC-MS: m/z = 456, Rt= 2.6 min Example 36 3-{2-[3-(4-trans-Isopropyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll 5 propionic acid

H

3 C CH 3 ".YN yNs OH

H

3 C 0

CH

3 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-isopropyl-cyclohexylamine hydrochlo ride, 1 -bromo-3-methylbutane and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 10 'H NMR (400 MHz, CDC1 3 ) 8 7.25 (s, 1 H), 3.65 (broad s, 1 H), 3.21 (m, 2H), 2.99 (broad m, 2H), 2.73 (m, 2H), 1.90 (m, 2H), 1.82 (m, 3H), 1.61 (m, 2H), 1.45 (m, 4H), 1.27 (m, 1 H), 1.04 (m, 1 H), 0.93 (d, 6H), 0.89 (s, 9H). HPLC-MS: m/z = 442, Rt= 2.5 min 15 Example 37 {2-[3-(4-Methyl-cyclohexyl)-3-(3-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid N0 N N S SHO

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid using 3-phenylpropionaldehyd, trans-4-methyl-cyclohexylamine and (2 20 amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1H), 7.32-7.25 (m, 5H), 4.10-3.9 (m, 1H), 3.48 (s, 2H), 3.3-3.2 (m, 2H), 2.59 (t, 2H), 1.95-0.95 (m, 11 H), 0.87 (d, 3H) HPLC-MS mlz= 448 (M+1) 25 Example 38 WO 2007/006814 PCT/EP2006/064289 100 {2-[3-(3-Methyl-butyl)-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsu Ifanyll acetic acid (General procedure (E), (A) and (B)) 5 CH 3 OH

H

3 C N S O H

H

3 0 General synthesis of trans-4-alkoxy-cyclohexylamine intermediates: Trans 4-aminocyclohexanol (25 g, 0.22 mol) dissolved in water (350 mL) was added potas sium carbonate (3.0 g, 0.022 mol) and N-carbethoxyphthalimide (47.6 g, 0.22 mol) and the 10 reaction mixture was stirred for 16 hours. The white precipitate was filtered off, washed with water and dried to give 37.7 g (71%) of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (J. Med. Chem. 1996, 39, 314-322 ). To a solution of trans-2-(4-hydroxycyclohexyl)-isoindole-1,3-dione (13 g, 53 mmol) in dry 15 DMF (50 mL) was added molecular sieves (4A, 6 mL). The mixture was stirred for 30 min at rt. NaH (5.3 g 60% in oil, 132.5 mmol) was washed with hexanes before it was added in por tions to the reaction mixture. The mixture was stirred for 30 min before propylbromide (48.1 mL, 530 mmol) was added. The reaction mixture was stirred for 16 hours before the reaction mixture was filtered. The filtrate was added water (100 mL) and extracted with Et 2 O (250 20 mL). The organic phase was washed with brine (3 x 50 mL) and dried (MgSO4) and the sol vent was removed in vacuo. The crude product was purified by column chromatography (sil ica gel, heptane-EtOAc (4:1). The first band was collected to give 6.6 g (43%) of trans-2-(4 propyloxycyclohexyl)-isoindole-1,3-dione. 'H-NMR (CDCI 3 ): 7.8 (s, 2H), 7.7 (s, 2H), 4.15 (m, 1H), 3.45 (t, 2H), 3.35 (m, 1H), 2.3 (m, 25 2H), 2.15 (m, 2H), 1.8 (m, 2H), 1.6 (h, 2H), 1.37 (m, 2H), 0.92 (t, 3H) Hydrazine hydrate (1.76 g, 55 mmol) was added to a solution of trans-2-(4 propyloxycyclohexyl)-isoindole-1,3-dione (7.90 g, 27.5 mmol) in absolute EtOH (100 mL). The reaction was stirred at 500C for 3h before the reaction mixture was filtered. The solvent WO 2007/006814 PCT/EP2006/064289 101 was removed in vacuo and Et 2 O (250 mL) was added after stirring for 30 min the solid was filtered off and the filtrate was added 150 mL 1 N HCI, the phases were separated and the aquous phase was washed with Et 2 O (150 mL) before 10 N NaOH was added (until pH =11 12). The aquous phase was extracted with EtOAc (200 mL + 2 x 100 mL) and the organic 5 fractions were collected and dried (MgSO 4 ) to give 3.11 g (72%) of trans-4-propoxy cyclohexylamine. 'H-NMR (CDC1 3 ): 3.4 (t, 2H), 3.18 (m, 1H), 2.7 (m, 1H), 2.0 (m, 2H), 1.85 (m, 2H), 1.55 (h, 2H), 1.4-1.1 (m, 4H), 0.9 (t, 3H). 10 (Reductive amination, coupling and hydrolysis): {2-[3-(3-Methyl-butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-propoxy-cyclohexylamine and (2-amino th iazol-5-ylsu lfanyl)-acetic acid ethyl ester. 15 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 4.1-3.9 (m, 1H), 3.48 (s, 2H), 3.25-3.15 (m, 3H), 2.05-1.95 (m, 2H), 1.7-1.2 (m, 13H), 0.90 (d, 6H), 0.87 (t, 3H). HPLC-MS: mlz= 444 (M+1) Example 39 20 {2-[3-(trans-4-tert-B utoxy-cyclohexyl)-3-(3-methyl-butyl)-u re ido]-th iazol-5-ylsulfanyl } acetic acid

CH

3 OH H3C N SO H

H

3 C OH

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-tert-butoxy-cyclohexylamine and (2 25 amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.00-3.38 (m, 1 H), 3.48 (s, 2H), 3.5-3.3 (m, 1 H), 3.25-3.15 (m, 2H), 1.8-1.2 (m, 11H), 1.15 (s, 9H), 0.90 (d, 6H). HPLC-MS: mlz= 458 (M+1) WO 2007/006814 PCT/EP2006/064289 102 Example 40 {2-[3-(trans-4-Cyclopropylmethoxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid

CH

3 OH H3CN S O H 5 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-cyclopropylmetoxy-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(3-methyl butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid) and (2-amino-thiazol 5-ylsulfanyl)-acetic acid ethyl ester. 10 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.05-1.90 (m, 1 H), 3.48 (s, 1 H), 3.23 (d, 2H), 3.25-3.15 (m, 3H), 2.05-1.95 (m, 2H), 1.70-1.15 (m, 9H), 1.0-0.9 (m, 1 H), 0.90 (d, 6H), 0.48 0.40 (m, 2H), 0.18-0.10 (m, 2H). HPLC-MS: mlz= 456 (M+1) 15 Example 41 {2-[3-[trans-4-(2-Methoxy-ethoxy)-cyclohexyl]-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid

CH

3 OH

H

3 C N H 6S 0 f

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 20 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-(2-methoxy-ethoxy)-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(3-methyl- WO 2007/006814 PCT/EP2006/064289 103 butyl)-3-(4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid) and (2-amino-thiazol 5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.05-3.85 (m, 1 H), 3.05-3.38 (m, 4H), 3.49 (s, 2H), 3.25 (s, 3H), 3.28-3.15 (m, 3H), 2.05-1.95 (m, 2H), 1.65-1.15 (m, 10H), 0.90 (d, 6H). 5 HPLC-MS: mlz= 460 (M+1) Example 42 {2-[3-(trans-4-Benzyloxy-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid

CH

3 OH

H

3 CN S H 0 10 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-benzyloxy-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(3-methyl-butyl)-3-(4 propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid) and (2-amino-thiazol-5 15 ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 7.38-7.23 (m, 5H), 4.50 (s, 2H); 4.05-3.95 (m, 1 H); 3.48 (s, 2H), 3.40-3.25 (s, 1 H), 3.25-3.15 (m, 2H); 2.12-2.02 (m, 2H), 1.70-1.28 (m, 9H), 0.88 (d, 6H). HPLC-MS: mlz= 492 (M+1) 20 Example 43 {2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid (General procedure (D), (A) and (B)) 25 WO 2007/006814 PCT/EP2006/064289 104

CH

3 OH

H

3 CN S H 0

CH

3 Preparation of trans-4-alkoxymethyl-cyclohexyl amine: A mixture of 4-carboxymethylcyclohexanone (21 g), ethylene glycol (19 g) and benzene (250 5 mL) was heated at reflux for 20 h with Dean Stark azeotropic removal of water. After cooling the solution was washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The crude ketal was then taken up in diethyl ether (250 mL) and lithium aluminium hydride (7 g) was added. The mixture was stirred overnight and then water (20 mL), 10% sodium hydroxide (30 mL) and water (30 mL) was added carefully. Sodium sul 10 phate (30 g) was then added and the mixture stirred for 20 min, The insoluble material was removed by filtration and the organic phase concentrated in vacuo to give (1,4-dioxa spiro[4.5]dec-8-yl)-methanol (21 g). 'H NMR (400 MHz, CDC1 3 ) 8 1.20-1.80, (m, 10H), 3.45 (d, 2H), 3.95 (s, 4H) 15 To (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (10 g) in tetrahydrofuran (300 mL) in an ice bath was added sodium hydride (3.6 g of 60% in mineral oil) and the mixture stirred for 30 min. Methyl iodide7.8 mL in THF (20 mL) was added dropwise and the rection was allowed to warm slowly to room temperature overnight.. Water (20 mL) was added and the reaction mix ture partially concentrated, then partitioned between water (100 mL) and diethyl ether (300 20 mL). The organic phase was isolated, dried and concentrated in vacuo. The crude was then taken up in tetrahydrofuran (250 mL) and 40 mL of 3N aqueous HCI was added. The reaction was stirred for 2h at room temperature, partially concentrated and then the crude product was extracted with diethyl ether, dried, concentrated and purified by flash chromatography (4 hexane: 1 ethyl acetate) to give 4-methoxymethyl-cyclohexanone 4.9 g. 25 'H NMR (400 MHz, CDC1 3 ) 8 1.40-1.55 (m, 2H), 1.98-2.15 (m, 3H), 2.20-2.45 (m, 4H), (d, 2H), 3.36 (d, 4H), 3.31 (s. 3H). A mixture of 4-methoxymethyl-cyclohexanone (5 g), hydroxylamine hydrochloride (4.7 g), and sodium acetate (5.6 g) in water (125 mL) and methanol (25 mL) was heated to 600C for WO 2007/006814 PCT/EP2006/064289 105 18h. ether was added and the organic phase isolated, washed with saturated sodium bicar bonate, dried over magnesium sulphate and concentrated in vacuo. Ethanol was added and then sodium (8 g) was added portion wise. The mixture was then heated to 650C for 1.5h, cooled in an ice bath and water (10 mL) was carefully added. The reaction was partially con 5 centrated, water (30 mL) was added and the aqueous phase was extracted with diethyl ether and concentrated to give the crude product. Addition of 6N HCI afforded the corresponding HCI salt which was recrystallised from acetonitrile to give trans-4-methoxymethyl cyclohexylamine hydrochloride (3 g). 'H NMR (400 MHz, DMSO-d) 8 0.90-1.15 (m, 2H), 1.20-1.37 (m, 2H), 1.38-1.54 (m, 1H), 10 1.73 (d, 2H), 1.95 (d, 2H), 2.80-2.95 (m, 1H), 3.12 (d, 2H), 3.22 (s. 3H), 8.21 (s, 3H). (Reductive amination, coupling and hydrolysis): {2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl 15 ureido)-thiazol-5-ylsulfanyl]-acetic acid using, trans-4-methoxymethyl-cyclohexylamine, isovaleraldehyde and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 4.02-3.95 (m, 1H), 3.48 (s, 2H), 3.28-3.17 (m, 2H), 3.23 (s, 3H), 3.13 (d, 2H), 1.80-1.30 (m, 1OH), 1.15-0.98 (m, 2H), 0.90 (d, 6H). HPLC-MS: mlz= 430 (M+1) 20 Example 44 {2-[3-(trans-4-Ethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid

CH

3 OH

H

3 CN S H H3C 25 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-ethoxymethyl-cyclohexylamine (pre pared in accordance with the general method given for the preparation of {2-[3-(4 methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid ) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 106 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.10-3.90 (m, 1 H), 3.48 (s, 2H), 3.38 (q, 2H), 3.26-3.15 (m, 2H), 3.18 (d, 2H), 1.80-1.70 (m, 2H), 1.70-1.30 (m, 9H), 1.10 (t, 3H), 0.90 (d, 6H) HPLC-MS: mlz= 444 (M+1) 5 Example 45 {2-[3-(trans-4-Cyclopropylmethoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid CH, OH HC Ok N: S_ AN ss O H 0 10 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyd, trans-4-cyclopropyl-methoxymethyl cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid ) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 15 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.05-3.90 (m, 1 H), 3.48 (s, 2H), 3.25-3.50 (m, 6H)1.85-0.95 (m, 13H), 0.90 (d, 6H), 0.50-0.40 (m, 2H), 0.20-0.10 (m, 2H) HPLC-MS: mlz= 470 (M+1) Example 46 20 {2-[3-Butyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid

CH

3 OH N S H COH3 WO 2007/006814 PCT/EP2006/064289 107 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid using butyraldehyd, trans-4-methyl-cyclohexylamine and (2-amino th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 4.00-3.88 (m, 1H), 3.48 (s, 2H), 3.25-3.15 (m, 5 2H), 1.75-0.95 (m, 13H), 0.93-0.81 (m, 6H) HPLC-MS: mlz= 386 (M+1) Example 47 {2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

CH

3 OH N N S H 10

H

3 C CH 3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid using isovaleraldehyde, 3-methylbutylamine and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 3.49 (s, 2H), 3.40-3.20 (m, 4H), 1.60-1.49 (m, 15 2H), 1.42-1.33 (m, 4H), 0.90 (d, 12H). HPLC-MS: mlz= 374 (M+1) Example 48 {2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid

CH

3 OH N N S O 20

H

3 C Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid using isovaleraldehyde, butylamine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 3.48 (s, 2H); 3.35-3.2 (m, 4H), 1.60-1.20 (m, 25 7H), 0.92-0.82 (m, 9H). HPLC-MS: mlz= 360 (M+1) WO 2007/006814 PCT/EP2006/064289 108 Example 49 3-{2-[3,3-Bis-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}- propionic acid CH 0

H

3 C N OH N aN S ZH

H

3 C

CH

3 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 5 ylsu lfanyl]-acetic acid using isovaleraldehyde, 3-methyl-butylamine and (2-amino-thiazol-5 ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.39 (s, 1 H), 3.40-3.28 (m, 4H), 2.84 (t, 2H), 2.50 (t, 2H), 1.61-1.49 (m, 2H), 1.42-1.32 (m, 4H), 0.89 (d, 6H). HPLC-MS: mlz= 388 (M+1) 10 Example 50 2-[3-(4-trans-Ethyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid O N_ OH N N s H C 15 Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 2 bromoethoxybenzene and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.30-7.25 (m. 3H), 6.97-6.88 (m, 3H), 4.11 (m, 3H), 3.71 (m, 2H), 3.27 (s, 2H), 1.84 (m, 4H), 1.56 (m, 2H), 1.25-1,10 (m, 7H), 0.88 (m, 4H). 20 HPLC-MS: mlz= 464 (M+1) Example 51 {2-[3-(4-trans-Ethyl-cyclohexyl)-3-(4-phenoxy-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 109 0 N _ N 21 OH b H HC Prepared as described for the synthesis of {2-[3-(4-trans-ethyl-cyclohexyl)-3-(3-methyl-butyl) u reido]-th iazol-5-ylsu Ifanyll-acetic acid, from 4-trans-ethyl-cyclohexylamine hydrochloride, 4 bromobutoxybenzene and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, CDC1 3 ) 8 7.30-7.23 (m, 3H), 6.95-6.85 (m, 3H), 3.99 (m, 3H), 3.33 (m, 2H), 3.30 (s, 2H), 1.87-1.75 (m, 8H), 1.50 (m, 2H), 1.23 (m, 2H), 1.08 (m, 2H), 0.88 (t, 3H). HPLC-MS: mlz= 514 (M+1) Example 52 10 3-{2-[3-Butyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyll propionic acid CH 0 HC 0OH N N SO

H

3 C H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid using isovaleraldehyde, butylamine and (2-amino-thiazol-5-ylsulfanyl) 15 propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 7.39 (s, 1 H), 3.80-3.25 (m, 4H), 2.84 (t, 2H), 2.50 (t, 2H), 1.60 1.20 (7H), 0.95-0.84 (m, 9H). HPLC-MS: mlz= 374 (M+1) 20 Example 53 2-Methyl-2-{2-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid WO 2007/006814 PCT/EP2006/064289 110 N N S O 0H ~OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and 2-(2 amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d 6 ) 8 7.40 (s, 1 H), 3.97 (m, 1 H), 3.21 (m, 2H), 1.75-1.25 (m, 10 H), 1.39 (s, 6H), 1.15-1.00 (m, 2H), 0.90 (d, 6H), 0.87 (d, 3H) HPLC-MS: m/z = 428 Example 54 10 2-{2-[3-Cyclohexyl-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid 00 N J N S 0 H S OH Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsulfanyl]-acetic acid, from cyclohexanone, 3-methylbutylamine and 2-(2-amino-thiazol-5 15 ylsulfanyl)-2-methyl-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 3.97 (m, 1 H), 3.23 (m, 2H), 1.80-1.00 (m, 13H), 1.40 (s, 6H) HPLC-MS: m/z = 415 20 Example 55 5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazole-2 carboxylic acid ethyl ester WO 2007/006814 PCT/EP2006/064289 111 N N ')S H O Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and 5-amino [1,3,4]thiadiazole-2-carboxylic acid ethyl ester. 5 HPLC-MS: m/z = 383 Example 56 {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-acetic acid ethyl ester o N-N 0 10 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and (5-amino [1,3,4]thiadiazol-2-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 429 15 Example 57 2-Methyl-2-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol 2-ylsulfanyl}-propionic acid O N-N "_ N N J"S O OH 20 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and (2-(2 amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester. HPLC-MS: m/z = 429 WO 2007/006814 PCT/EP2006/064289 112 Example 58 {5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-acetic acid O N--N " N N S S O OH 5 Prepared by hydrolysis of {5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4 thiadiazol-2-ylsulfanyl}-acetic acid ethyl ester described for the synthesis of [2-(3-cyclohexyl 3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid. HPLC-MS: m/z = 401 10 Example 59 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-propionic acid ethyl ester N S 0 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 15 ylsulfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and 3-(5 amino-[1,3,4]thiadiazol-2-ylsulfanyl)-propionic acid ethyl ester HPLC-MS: m/z = 443 Example 60 20 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazo-2-yl} propionic acid methyl ester H 0 Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine, isovaleraldehyde and 3-(5 25 amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester WO 2007/006814 PCT/EP2006/064289 113 HPLC-MS: m/z = 397 Example 61 {2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll 5 acetic acid OH N S 0 H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu lfanyl]-acetic acid from (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and (2 amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester 10 'H NMR (400 MHz, DMSO-d) 8 7.38 (s, 1 H), 3.68-3.55 (m, 1 H), 3.50-3.20 (m, 1 H), 3.48 (s, 2H), 1.80-0.95 (m, 15H), 0.92-0.80 (m, 9H) HPLC-MS: m/z = 415 15 Preparation of (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine: 4-trans-methyl-cyclohexylamine hydrochloride (3.74, 24.96 mmol) in anhydrous MeOH (40 mL) was added NaOH (1.0 g, 24.96 mmol) followed by isobutylmethylketone (2.5 g, 24.96 mmol) and the reaction mixture was stirred for 30 min before glacial acetic acid (15 mL), and Pd/C (10%, 375 mg) was added. The reaction mixture was stirred at room temperature under 20 H 2 (1 atm) for 18 hours before more isobutylmethylketone (1.25 g, 12.48 mmol) was added. The reaction was then left stirring under H 2 for 72 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo, dissolved in diethyl ether and washed twice with saturated sodium bicarbonate (50 mL). The organic phase was acidified by adding 1 N HCI in diethyl ether (25 mL). The precipitated product was collected by filtration to give 2.9 g 25 of (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine. Example 62 2-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5-ylsulfanyl} 2-methyl-propionic acid WO 2007/006814 PCT/EP2006/064289 114 o N &OH U N N 'XS OOH H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid from (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and (2-(2 amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester 5 'H NMR (400 MHz, DMSO-d) 8 7.35 (s, 1H), 3.60-3.10 (m, 2H), 1.72-0.95 (m, 15H), 1.38 (s, 6H), 0.92-0.82 (m, 9H) HPLC-MS: m/z = 443 Example 63 10 3-{2-[3-(1,3-Dimethyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5-ylsulfanyl} propionic acid 0 N N OH H Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5 ylsu Ifanyl]-acetic acid from (1,3-dimethyl-butyl)-(4-trans-methyl-cyclohexyl)-amine and (2 15 amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.35 (s, 1 H), 2.83 (t, 2H), 2.49 (t, 2H), 1.75-0.95 (m, 15H), 0.91-0.82 (m, 9H) HPLC-MS: m/z = 429 20 Example 64 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2 ylsulfanyl}-propionic acid N S OH 6H WO 2007/006814 PCT/EP2006/064289 115 Prepared by hydrolysis of 3-{5-[3-(3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido] 1,3,4-thiadiazol-2-ylsulfanyl}-propionic acid ethyl ester as described for the preparation of [2 (3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid HPLC-MS: m/z = 415 5 Example 65 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-1,3,4-thiadiazol-2-yl} propionic acid 0 N OH H O 10 Prepared by hydrolysis of 3-{5-[3-(3-Methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido] 1,3,4-thiadiazol-2-yl}-propionic acid methyl ester as described for the preparation of [2-(3 cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid HPLC-MS: m/z = 383 15 Example 66 {2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5-ylsulfanyl} acetic acid OH O,-'N N S O H To a solution of 2-benzyloxyethanol (305 mg, 2.0 mmol) and DIPEA (0.69 mL, 4.0 mmol) in 20 DCM (5 mL) cooled on an ice bath was added mesylchloride (0.19 mL, 2.5 mmol). The reac tion mixture was stirred for 15 min before the ice bath was removed. After stirring for an addi tional 45 min the reaction mixture was washed with aqueous HCI (0.1 N, 5 mL). The aqueous phase was extracted with dichloromethane (2 x 5 mL) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. 25 The residue was dissolved in acetonitrile (5 mL) before DIPEA (0.34 mL, 2.0 mmol) and 4 trans-methyl-cyclohexylamine (226 mg, 2.0 mmol) were added. The reaction mixture was refluxed for 18 hours before the volatiles were removed in vacuo.

WO 2007/006814 PCT/EP2006/064289 116 The residue was dissolved in tetrahydrofuran (2 mL) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (655 mg, 3.0 mmol), carbonyl diimidazole (487 mg, 3.0 mmol) and 4 (dimethylamino)pyridine (12 mg, 0.1 mmol) were added. The reaction mixture was stirred for 2 hours before the volatiles were removed in vacuo. 5 The residue was dissolved in methanol (2.5 mL) and NaOH (2N, 5 mL,1 0 mmol) was added. The mixture was stirred for 2 hours before HCI (1 mL, conc.) was added. The solvent was removed in vacuo before tetrahydrofuran, 5 mL) was added and the mixture was filtered. The filtrate was purified on a preparative HPLC to give 230 mg {2-[3-(2-benzyloxy-ethyl)-3-(4 trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid. 10 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 7.35-7.23 (m, 5H), 4.53 (s, 2H), 3.92 (m, 1 H), 3.57-3.44 (m, 6H), 1.73-1.45 (m, 6H), 1.35-1.25 (m, 1 H), 1.10-0.95 (m, 1 H), 0.86 (d, 3H) HPLC-MS: m/z = 465 Example 67 15 {2-[3-(2-Isopropoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5-ysu Ifanyl} acetic acid OH 0,-'N A N i S ')S O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-isopropoxyethanol, 4-trans 20 methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 4.0-3.84 (m, 1 H), 3.70-3.20 (m, 7H), 1.80-0.93 (m, 18H) (with the following distinct signal: 1.12 (d, 6H)), 0.86 (d, 3H) HPLC-MS: m/z = 417 25 Example 68 {2-[3-(2- tert-B utoxy-ethyl)-3-(4- trans-methyl-cyclohexyl)-u reido]-th iazo l-5-ylsu Ifanyl} acetic acid OH O N O H-N N S S O

H

WO 2007/006814 PCT/EP2006/064289 117 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-tert-butoxyethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 3.92 (t, 1 H), 3.53-3.33 (m, 6H), 1.75-1.25 (m, 5 7H), 1.19 (s, 9H), 1.10-0.95 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 431 Example 69 {2-[3-(2-Cyclohexyloxy-ethyl)-3-(4- trans-methyl-cyclohexyl)-u reido]-th iazol-5 10 ylsulfanyl}-acetic acid OH Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-cyclohexyloxyethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 15 HPLC-MS: m/z = 457 Example 70 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid FF O N -\0H tF OH F F H 20 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2,2,2-trifluoro-1 -trifluoromethyl ethoxy)-ethanol, 4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 25 HPLC-MS: m/z = 525 Example 71 WO 2007/006814 PCT/EP2006/064289 118 {2-[3-(2-Ethoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5-ylsu Ifanyl}-acetic acid ON OH -"O, N IkN 111S S O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 5 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-ethoxyethanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 403 Example 72 10 {2-[3-(2-Iso-butoxy-ethyl)-3-(4- trans-methyl-cyc Iohexyl)-u reido]-th iazol-5-ylsulfanyl } acetic acid OH O,-^N JlN ilS O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-isobutoxyethanol, 4-trans-methyl 15 cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 431 Example 73 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5 20 ylsulfanyl)-acetic acid FE OH F-<O,-'^N ' N kS O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2,2,2-trifluoroethoxyethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 25 HPLC-MS: m/z = 457 WO 2007/006814 PCT/EP2006/064289 119 Example 74 {2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid 0N OH N NN S SO O H 5 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-methoxy-3-methylbutan-1 -ol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.41 (s, 1 H), 4.04-3.91 (m, 1 H), 3.47 (s, 2H), 3.47-3.27 (m, 10 4H), 3.26-3.16 (m, 3H), 1.75-0.95 (m, 15H), (with following distinct signal: 1.13 (s, 6H)), 0.87 (d, 3H) HPLC-MS: m/z = 431 Example 75 15 3-{2-[3-(2-Benzyloxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5-ylsulfanyl} propionic acid 0 OH O 0 N O1H H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-benzyloxyethanol, 4-trans-methyl 20 cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester HPLC-MS: m/z = 479 Example 76 3-{2-[3-(2-Iso-propoxy-ethyl)-3-(4- trans-methyl-cyclohexyl)-u reido]-th iazo 1-5 25 ylsulfanyl}-propionic acid WO 2007/006814 PCT/EP2006/064289 120 0 0 N OH O,' N N S S H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-iso-propoxyethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 5 HPLC-MS: m/z = 431 Example 77 3-{2-[3-(2-tert-Butoxy-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} propionic acid 0 OH O N OH

S

0 ,-'N K N S S I OH 10 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-tert-butoxyethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 445 15 Example 78 3-{2-[3-(2-Cyclohexyloxy-ethyl)-3-(4- trans-methyl-cyc Iohexyl)-u reido]-th iazol-5 ylsulfanyl}-propionic acid H 20 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-cyclohexyloxyethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 471 WO 2007/006814 PCT/EP2006/064289 121 Example 79 3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-propionic acid 0 F F O N\OH F O,0-'''N N I F F H 5 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2,2,2-Trifluoro-1 -trifluoromethyl ethoxy)-ethanol, 4-trans-methyl-cyclohexylamine and. (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester. HPLC-MS: m/z = 539 10 Example 80 3-{2-[3-(2-Iso-butoxy-ethyl)-3-(4- trans-methyl-cyclohexyl)-u reido]-th iazol-5-ylsulfanyl} propionic acid OHO ,-'^',N IkN OH H 15 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-isobutoxyethanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 444 20 Example 81 3-(2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2,2,2-trifluoro-ethoxy)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-propionic acid 0 FF 0 N J0H

OH

WO 2007/006814 PCT/EP2006/064289 122 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2,2,2-trifluoroethoxyethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 471 5 Example 82 3-{2-[3-(3-Methoxy-3-methyl-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-propionic acid 0 0OH N N AS O0 H 10 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-methoxy-3-methylbutan-1 -ol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 445 15 Example 83 {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll acetic acid OH O Ng rd_ 0,-'^'N N S O OH Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 20 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-phenoxyethanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 451 Example 84 25 {2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsu Ifanyl} acetic acid WO 2007/006814 PCT/EP2006/064289 123 OH O N r_-j O'-''N N S S O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-ethoxypropanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 HPLC-MS: m/z = 417 Example 85 {2-[3-(3-Methoxy-butyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsu Ifanyl} acetic acid OH 'O N KN ILS O H 10 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-methoxy-butan-1 -ol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 417 15 Example 86 {2-[3-(3-Benzyloxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsu Ifanyl} acetic acid OH O Ng - OH O ^'''N II S O 20 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-benzyloxypropanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 479 25 Example 87 WO 2007/006814 PCT/EP2006/064289 124 3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenoxy-ethyl)-ureido]-thiazol-5-ylsulfanyll propionic acid 0 O N OH s -'''N KN JS" H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 5 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-phenoxyethanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 465 Example 88 10 3-{2-[3-(3-Ethoxy-propyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} propionic acid O N OH 'O' '^' N N1 H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-ethoxypropanol, 4-trans-methyl 15 cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 431 Example 89 {2-[3-(2-Benzyloxy-1 -methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 20 ylsulfanyl}-acetic acid OH 0 OLN 'kN 'jS O H Benzyloxyacetone (0.50 g, 3.0 mmol) and 4-trans-methyl-cyclohexylamine (0.313 g, 2.79 mmol) in THF-MeOH (50 mL, 2:1) and AcOH (5 mL) was added sodium cyanoborohydride (0.26 g, 4.15 mmol) in small portions over 15 min. The reaction mixture was stirred for 16 WO 2007/006814 PCT/EP2006/064289 125 hours before the solvent was removed in vacuo. The residue was divided between Et 2 O (150 mL) and aqueous NaOH (10 M, 50 mL). The aqueous phase was extracted twice with Et 2 O (100 mL), and the combined organic extracts were dried (MgSO4), filtered and dried in vacuo to give (2-benzyloxy-1 -methyl-ethyl)-(4-trans-methyl-cyclohexyl)-amine. 5 {2-[3-(2-Benzyloxy-1 -methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll acetic acid was then prepared using the procedure described for the synthesis of [2-(3 cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid from (2-benzyloxy-1 -methyl ethyl)-(4-trans-methyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl 10 ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 7.37-7.22m, 5H), 4.5 (s, 2H), 4.0-3.4 (m, 4H), 1.90-1.48 (m, 6H), 1.39-1.22 (m, 4H), 1.15-0.97 (2H), 0.87 (d, 3H) HPLC-MS: m/z = 478 15 Example 90 {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ysulfanyll acetic acid OH O Ng r\ O''-''N J N J1S "S O H Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 20 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-phenoxypropanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 464 Example 91 25 3-{2-[3-(2-Benzyloxy-1 -methyl-ethyl)-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-propionic acid 0 O N iNASS OH

H

WO 2007/006814 PCT/EP2006/064289 126 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-1 -methyl-ethyl)-3-(4-trans methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using benzyloacetone, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 492 5 Example 92 3-{2-[3-(4-trans-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyll propionic acid 0 OH '1 O- NI N OH S H 10 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-phenoxypropanol, 4-trans-methyl cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. HPLC-MS: m/z = 478 15 Example 93 {2-[3-[2-(2-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid CI N OH H S Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 20 cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-chloro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.46-7.22 (m, 5H), 4.05-3.92 (m, 1 H), 3.50 (s, 2H), 3.49-3.30 (m, 2H), 3.93 (t, 2H), 1.72-1.62 (m, 2H), 1.60-1.44 (m, 4H), 1.38-1.22 (m, 1H), 1.12-1.00 (m, 2H), 0.87 (d, 3H) 25 HPLC-MS: m/z = 468 Example 94 WO 2007/006814 PCT/EP2006/064289 127 {2-[3-[2-(3-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid CI NS OH H 0 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 5 cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(3-chloro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1 H), 7.42-7.22 (m, 4H), 4.05-3.95 (m, 1 H), 3.50 (s, 2H), 3.49-3.30 (m, 2H), 2.79 (t, 2H), 1.75-1.55 (m, 2H), 1.63-1.50 (m, 4H), 1.15-1.00 (m, 2H), 0.88 (d, 3H) 10 HPLC-MS: m/z = 468 Example 95 {2-[3-[2-(4-Chloro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid CI 0 N NN S OH H 15 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-chloro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1 H), 7.38-7.28 (m, 4H), 4.07-3.92 (m, 1 H), 3.50 (s, 20 2H), 3.46-3.35 (m, 2H), 2.79 (t, 2H), 1.72-1.65 8M, 2H), 1.60-1.50 (m, 4H), 1.40-1.28 (m, 1 H), 1.12-0.90 (m, 2H)0.87 (d, 3H) HPLC-MS: m/z = 469 Example 96 WO 2007/006814 PCT/EP2006/064289 128 {2-[3-[2-(2-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid 0N SX OH H 0 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 5 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2-methoxy-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.45 (s, 1H), 7.28-7.18 (m, 2H), 7.01-6.98 (m, 1H), 6.92-6.85 (m, 1 H), 4.08-3.93 (m, 1 H), 3.89 (s, 3H), 3.50 (s, 2H), 3.40-3.30 (m, 2H), 2.80-2.74 (m, 2H), 1.73-1.68 (m, 2H), 1.62-1.52 (m, 4H), 1.40-1.25 (m, 1H), 1.12-1.00 (m, 2H), 0.89 (d, 3H) 10 HPLC-MS: m/z = 464 Example 97 {2-[3-[2-(3-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid 0 N S OH H 0 15 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(3-methoxy-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.29-7.19 (m, 2H), 6.90-6.82 (m, 2H), 6.79-6.72 (m, 1H), 3.80 20 (s, 3H), 3.57-3.45 (m, 2H), 3.32 (s, 2H), 2.92-2.83 (m, 2H), 1.87-1.73 (m, 4H), 1.62-1.48 (m, 2H), 1.42-1.29 (m, 1 H), 1.28-1.09 (m, 2H), 0.92 (d, 3H) HPLC-MS: m/z = 464 Example 98 WO 2007/006814 PCT/EP2006/064289 129 {2-[3-[2-(4-Methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid

I

0 N NI S OH H 0 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 5 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-methoxy-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.38 (s, 1 H), 7.22 (d, 2H), 6.83 (d, 2H), 4.20-3.90 (m, 1 H), 3.79 (s, 3H), 3.55-3.42 (m, 2H), 3.38 (s, 2H), 2.90-2.80 (m, 2H), 1.85-1.72 (m, 4H), 1.62-1.48 (m, 2H), 1.40-1.05 (m, 3H), 0.92 (d, 3H) 10 HPLC-MS: m/z = 464 Example 99 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(1 -phenyl-ethoxy)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid NN 0 0 H S 0 OH 15 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-u reido]-th iazol-5-ylsu Ifanyll-acetic acid using 2-(1 -phenyl-ethoxy)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.39 (s, 1 H), 7.37-7.22 (m, 4H), 4.43 (q, 1 H), 4.20-4.00 (m, 1 H), 20 3.50-3.40 (m, 4H), 3.38 (s, 2H), 1.78-1.56 (m, 4H), 1.48 (d, 3H)1.43-1.00 (m, 5H), 0.87 (d, 3H) HPLC-MS: m/z = 478 Example 100 WO 2007/006814 PCT/EP2006/064289 130 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethylsulfanyl-benzyloxy)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid F F OH O,-'^O'N KN 'j-' O H Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) 5 ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2 trifuoromethylthio-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.73-7.68 (m, 1 H), 7.65-7.61 (m, 1 H), 7.59-7.53 (m, 1 H), 7.49-7.43 (m, 1 H), 7.39 (s, 1 H), 4.72 (s, 2H), 3.99-3.87 (m, 1 H), 3.63-3.57 (m, 2H), 3.54-3.47 10 (m, 2H), 3.48 (s, 2H), 1.71-1.46 (m, 6H), 1.36-1.23 (m, 1H), 1.10-0.96 (m, 2H), 0.86 (d, 3H) HPLC-MS: m/z = 564 Example 101 {2-[3-[2-(2-Cyano-benzyloxy)-ethyl]-3-(4- trans-methyl-cyclohexyl)-u reido]-th iazo 1-5 15 ylsulfanyl}-acetic acid N O AN S 0 H

CH

3 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-cyano benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester 20 and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.85-7.81 (m, 1 H), 7.70-7.59 (m, 2H), 7.53-7.46 (m, 1 H), 7.39 (s, 1 H), 4.69 (s, 2H), 3.99-3.87 (m, 1 H), 3.65-3.58 (m, 2H), 3.54-3.46 (m, 2H), 3.48 (s, 2H), 1.72-1.46 (m, 6H), 1.36-1.23 (m, 1 H), 1.10-0.95 (m, 2H), 0.86 (d, 3H) HPLC-MS: m/z = 489 25 Example 102 WO 2007/006814 PCT/EP2006/064289 131 {2-[3-[2-(4-Fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl) ureido]-thiazol-5-ylsulfanyll-acetic acid F F OH H CH A refluxing solution of 4-trans-methyl-cyclohexylamine hydrochloride (13.9 g, 93 mmol) and 5 potassium carbonate (25.6 g, 186 mmol) in acetonitrile (100 mL) was added a solution of 2 (benzyloxy)-ethylbromide (20 g, 93 mmol) in acetonitrile (50 mL) over the course of 30 min. The mixture was refluxed for 2 hours before it was allowed to reach room temperature whereupon a solution of di-tert-butyl-dicarbonate (1 M, THF, 93 mL) was added. The reaction mixture was stirred at room temperature for 18 hous before the volatiles were removed in 10 vacuo. The residue was dissolved in diethyl ether (150 mL) and washed with water (2 x 100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , heptane to 10% EtOAc in heptane) to give 23.7 g of (2-benzyloxy ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester. This was dissolved in abs. ethanol (250 mL) and Pd/C (10%, 2.0 g) was added. The reaction 15 mixture was stirred under H 2 at room temperature for 4 hours before it was filtered through a pad of Celite and subsequently concentrated in vacuo to give 17.5 g of (2-hydroxy-ethyl)-(4 trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester. (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester (500 mg, 1.94 20 mmol) and 4-fluoro-2-trifluoromethyl-benzylbromide (500 mg, 2.33 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 155 mg, 3.89 mmol) and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was divided (caution!) between hex ane (50 mL) and water (50 mL). The aqueous phase was extracted twice with hexane (50 mL) and the combined organic fractions were dried (MgSO 4 ) and concentrated in vacuo. The 25 residue was stirred in a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) for 2 hours before the volatiles were removed in vacuo. The residue was purified by prep. HPLC to give 500 mg of [2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-(4-trans-methyl-cyclohexyl) amine. 30 {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid was prepared as described for the synthesis of [2-(3- WO 2007/006814 PCT/EP2006/064289 132 cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid from [2-(4-fluoro-2 trifluoromethyl-benzyloxy)-ethyl]-(4-trans-methyl-cyclohexyl)-amine and 5-amino [1,3,4]thiadiazole-2-carboxylic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.78-7.22 (m, 1H), 7.65-7.59 (m, 1H), 7.55-7-48 (m, 1H), 7.40 (s, 1 H), 4.65 (s, 2H), 4.00-3.87 (m, 1 H), 3.62-3.55 (m, 2H), 3.54-3.48 (m, 2H), 3.48 (s, 2H), 1.72-1.45 (m, 6H), 1.38-1.18 (m, 1 H), 1.10-0.95 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 550 10 Example 103 {2-[3-[2-(4-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid F H s O OH CH, Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 15 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-fluoro-phenyl)-ethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.28-7.22 (m, 3H), 7.02-6.95 (m, 2H), 4.15-3.80 (m, 1H), 3.52 3.40 (m, 2H), 3.33 (s, 2H), 2.92-2.83 (m, 2H), 1.83-1.72 (m, 4H), 1.60-1.43 (m, 2H), 1.43 1.10 (m, 3H), 0.92 (d, 3H) 20 HPLC-MS: m/z= 452 Example 104 {2-[3-[2-(2-Fluoro-6-trifluoromethyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl) ureido]-thiazol-5-ylsulfanyll-acetic acid F OH N S F H 25 CH 3 WO 2007/006814 PCT/EP2006/064289 133 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-fluoro-6 trifluoromethyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 HPLC-MS: m/z = 550 Example 105 {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyll acetic acid CH 6 H O OH 10 CH 3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-phenyl-propan-1 -ol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.32-7.12 (m, 6H), 3.85-3.70 (m, 1H), 3.65-3.55 (m, 1H), 3.35 15 (s, 2H), 3.30-3.08 (m, 2H), 1.80-1.00 (m, 12H, with following distinct signal; 1.31 (d, 3H)), 0.88 (d, 3H) HPLC-MS: m/z= 448 Example 106 20 {2-[3-[2-(2-Chloro-4-fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid F CN OH N S H

CH

3 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-chloro-4 25 fluoro-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 134 'H NMR (400 MHz, DMSO-d) 8 7.83-7.76 (m, 1H), 7.71-7.67 (m, 1H), 7.65 (s, 1H), 7.48-7.40 (m, 1H), 4.82 (s, 2H), 4.24-4.12 (m, 1H), 3.88-3.80 (m, 2H), 3.78-3.72 (m, 2H), 3.73 (s, 2H), 1.98-1.47 (m, 8H), 1.37-1.20 (m, 2H), 1.11 (d, 3H) HPLC-MS: m/z= 517 5 Example 107 {2-[3-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid yH3 0 N N-JI S 6H O OH

CH

3 10 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3,4-dimethoxy-phenyl-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.27 (s, 1 H), 6.82-6.76 (m, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.54 3.44 (m, 2H), 3.32 (s, 2H), 2.89-2.80 (m, 2H), 1.85-1.72 (m, 4H), 1.62-1.48 (m, 2H), 1.42 15 1.10 (m, 3H), 0.92 (d, 3H) HPLC-MS: m/z= 494 Example 108 {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-p-tolyl-ethyl)-ureido]-thiazol-5-ylsulfanyll-acetic 20 acid

H

3 C N _S H O OH CH, Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4-methyl-phenyl-ethanol, 4-trans methyl-cyclohexylamine and (2-amino-th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 135 'H NMR (400 MHz, CDC1 3 ) 8 7.26 (s, 1H), 7.18 (d, 2H); 7.11 (d, 2H), 4.3-3.8 (m, 1H), 3.52 3.43 (m, 2H), 3.32 (s, 2H), 2.90-2.82 (m, 2H), 2.32 (s, 3H), 1.87-1.72 (m, 4H), 1.62-1.47 (m, 2H), 1.42-1 .10 (m, 3H), 0.92 (d, 3H) HPLC-MS: m/z= 448 5 Example 109 {2-[3-(4-trans-methyl-cyclohexyl)-3-(2-pentafluorophenylmethoxy-ethyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid F F F OH FH CH, 10 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 1,2,3,4,5 pentafluoro-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z= 554 15 Example 110 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-ureido}-thiazol 5-ylsulfanyl)-acetic acid F F F H O OH

CH

3 20 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-u reido]-th iazol-5-ylsu Ifanyll-acetic acid using 4-trifluoromethyl-phenyl-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-th iazol-5-ylsu Ifanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.67 (d, 2H), 7.52 (d, 2H), 7.43 (s, 1H), 4.05-3.92 (m, 1H), 3.50 (s, 2H), 3.50-3.42 (m, 2H), 2.92-2.85 (m, 2H), 1.73-1.65 (m, 2H), 1.62-1.50 (m, 4H), 25 1.40-1.25 (m, 1 H), 1.13-0.98 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 502 WO 2007/006814 PCT/EP2006/064289 136 Example 111 {2-[3-[2-(4-Ethoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid

H

3 C 0 N - S HO OH 5 CH, Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-ethoxy-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.42 (s, 1H), 7.18 (d, 2H), 6.85 (d, 2H), 4.03-3.92 (m, 3H), 10 3.50 (s, 2H), 3.42-3.40 (m, 2H), 2.75-2.67 (m, 2H), 1.73-1.63 (m, 2H), 1.62-1.59 (m, 4H), 1.39-1.28 (m, 4H), 1.12-1.00 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 478 Example 112 15 {2-[3-[2-(4-Isopropoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid HC CH, 0 N , S _ H O OH CH, Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-isopropoxy-phenyl)-ethanol, 4 20 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1H), 7.17 (d, 2H), 6.83 (d, 2H), 4.57 (h, 1H), 4.02 3.90 (m, 1H), 3.49 (s, 2H), 3.49-3.30 (m, 2H), 2.73-2.65 (m, 2H), 1.73-1.63 (m, 2H), 1.62 1.48 (m, 4H), 1.39-1.29 (m, 1H), 1.25 (d, 6H), 1.12-1.00 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 492 WO 2007/006814 PCT/EP2006/064289 137 Example 113 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-propoxy-phenyl)-ethyl]-ureido}-thiazol-5 ylsulfanyl)-acetic acid CH, 0 OO H O - OH 5 H3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(4-propoxy-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1H), 7.18 (d, 2H), 6.87 (d, 2H), 4.05-3.93 (m, 1H), 10 3.88 (t, 2H), 3.50 (s, 2H), 3.42-3.30 (m, 2H), 2.75-2.67 (m, 2H), 1.75-1.63 (m, 4H), 1.62-1.48 (m, 4H), 1.40-1.28 (m, 1H), 1.13-1.00 (m, 2H), 0.98 (t, 3H), 0.87 (d, 3H) HPLC-MS: m/z= 492 Example 114 15 {2-[3-[2-(2-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid F ' NS H O OH CH3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2-fluoro-phenyl)-ethanol, 4-trans 20 methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1H), 7.40-7.32 (m, 1H), 7.32-7.22 (m, 1H), 7.19-7.12 (m, 2H), 4.06-3.94 (m, 1 H), 3.50 (s, 2H), 3.47-3.38 (m, 2H), 2.88-2.80 (m, 2H), 1.73-1.62 (m, 2H), 1.62-1.42 (m, 4H), 1.38-1.22 (m,1H), 1.13-0.97 (m, 2H), 0.88 (d, 3H) WO 2007/006814 PCT/EP2006/064289 138 HPLC-MS: m/z= 452 Example 115 {2-[3-[2-(3-Fluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 5 ylsulfanyl}-acetic acid F 0N S H O OH CH3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(3-fluoro-phenyl)-ethanol, 4-trans methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 10 'H NMR (400 MHz, DMDO-d) 8 7.42 (s, 1H), 7.38-7.30 (m, 1H), 7.19-7.10 (m, 2H), 7.08 7.00 (m, 1H), 4.05-3.93 (m, 1H), 3.49 (s, 2H), 3.48-3.39 (m, 2H), 2.83-2.77 (m, 2H), 1.73 1.65 (m, 2H), 1.62-1.50 (m, 4H), 1.42-1.29 (m, 1 H), 1.15-0.98 (m, 2H), 0.88 (d, 3H) HPLC-MS: m/z= 452 15 Example 116 {2-[3-[2-(4-Isopropyl-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid

CH

3

H

3 C J/N N , S H O OH

CH

3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 20 cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(3-isopropyl-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1H)7.22-7.15 (m, 4H), 4.03-3.90 (m, 1H), 3.50 (s, 2H), 3.45-3.35 (m, 2H), 2.85 (h, 1H), 2.78-2.70 (m, 2H), 1.72-1.64 (m, 2H), 1.63-1.48 (m, 4H), 1.39-1.26 (m, 1H), 1.18 (d, 6H), 1.13-0.98 (m, 2H), 0.87 (d, 3H) WO 2007/006814 PCT/EP2006/064289 139 HPLC-MS: m/z= 476 Example 117 {2-[3-[2-(3-Fluoro-4-methoxy-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] 5 thiazol-5-ylsulfanyll-acetic acid F

H

3 C "

J/N

N , S _ H O OH

CH

3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-u reido]-th iazol-5-ylsu Ifanyll-acetic acid using 2-(3-fluoro-4-methoxy-phenyl) ethanol, 4-trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl 10 ester. 'H NMR (400 MHz, DMSO-d) 8 7.43 (s, 1 H), 7.20-7.13 (m, 1 H), 7.12-7.00 (m, 2H), 4.04-3.93 (m, 1 H), 3.80 (s, 3H), 3.50 (s, 2H), 3.43-3.32 (m, 2H), 2.78-2.68 (m, 2H), 1.73-1.64 (m, 2H), 1.63-1.50 (m, 4H), 1.42-1.28 (m, 1H), 1.12-0.98 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z= 489 15 Example 118 {2-[3-[2-(3-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid OH 0 F N N O b H 20 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-fluoro benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1H), 7.39-7.33 (m, 1H), 7.18-7.05 (m, 3H), 4.55 (s, 25 2H), 3.99-3.85 (m, 1 H), 3.60-3.45 (m, 6H with to following distinct signal (3.49 (s, 2H)) HPLC-MS: m/z = 482 WO 2007/006814 PCT/EP2006/064289 140 Example 119 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethyl-benzyloxy)-ethyl]-ureido} thiazol-5-ylsulfanyl)-acetic acid OH F 0 ( ' XN'-"N N S F FH 5 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3 trifluoromethyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.70-7.52 (m, 4H), 7.39 (s, 1 H), 4.63 (s, 2H), 3.98-3.86 m, 10 1 H), 3.62-3.55 (m, 2H), 3.55-33.48 (m, 2H), 3.48 (s, 2H), 1.72-1.62 (m , 2H), 1.62-1.47 (m, 4H), 1.40-1.22 (m, 1H), 1.11-0.96 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 532 Example 120 15 {2-[3-[2-(4-Methanesulfonyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid O4 OH 0 1iu S O -C'. N N' S O H Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4 20 methylsulfonyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 532 Example 121 25 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethyl-benzyloxy)-ethyl]-ureido} thiazol-5-ylsulfanyl)-acetic acid WO 2007/006814 PCT/EP2006/064289 141 F F NOH N S H Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4 trifluoromethyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid 5 tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 532 Example 122 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(2-trifluoromethyl-benzyloxy)-ethyl]-ureido} 10 thiazol-5-ylsulfanyl)-acetic acid N 'KN OHS, H Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2 trifluoromethyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid 15 tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.74-7.18 (m, 2H), 7.68-7.58 (m, 1H),, 7.53-7.47 (m, 1H), 7.40 (s, 1 H), 4.69 (s, 2H), 4.00-3.88 (m, 1 H), 3.65-3.57 (m, 2H)3.57-3.49 (m, 2H), 3.49 (s, 2H), 1.72-1.63 (m, 2H), 1.62-1.47 (m, 4H), 1.38-1.20 (m, 1H), 1.10-0.97 (m, 2H), 0.87 (sd, 3H) 20 HPLC-MS: m/z = 532 Example 123 {2-[3-[2-(2-Methoxy-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid 0 N N OH 25 WO 2007/006814 PCT/EP2006/064289 142 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-methoxy benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 7.28-7.20 (m, 1 H), 6.92-6.87 (m, 2H), 6.85-6.80 (m, 1 H), 4.50 (s, 2H), 3.98-3.85 (m, 1 H), 3.8-3.4 (m, 9H, with the following distinct signals; 3.72 (s) and 3.50 (s)), 1.72-1.62 (m, 2H), 1.62-1.42 (m, 4H), 1.38-1.20 (m, 1 H), 1.10-0.93 (m, 2H), 0.88 (d, 3H) HPLC-MS: m/z = 494 10 Example 124 {2-[3-[2-(4-tert-Butyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid OH H 15 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4-tert butbyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 520 20 Example 125 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(4-trifluoromethoxy-benzyloxy)-ethyl]-ureido} thiazol-5-ylsulfanyl)-acetic acid F F FONN 0 N S O H 25 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4 trifluoromethoxy-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 548 WO 2007/006814 PCT/EP2006/064289 143 Example 126 {2-[3-[2-(2,4-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F OH FN N OH 5 H 5 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2,4 difluoro-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 10 HPLC-MS: m/z = 500 Example 127 {2-[3-[2-(4-Isopropyl-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid OH H 15 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3-isopropyl benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 20 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 7.28-7.13 (m, 4H), 4.49 (s, 2H), 3.98-3.35 (M, 1 H), 3.6-3.3 (m, 4H with the following distinct signal; 3.50 (s, 2H), 2.87 (h, 1 H), 1.72-1.60 (m, 2H), 1.60-1.39 (m, 4H), 1.37-1.22 (m, 1 H), 1.19 (d, 6H), 1.10-0.94 (m, 2H), 0.85 (d, 3H) HPLC-MS: m/z = 506 25 Example 128 {2-[3-[2-(4-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid WO 2007/006814 PCT/EP2006/064289 144 F OH H Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 4-fluoro benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester 5 and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 482 Example 129 (2-{3-(4-trans-methyl-cyclohexyl)-3-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-ureido} 10 thiazol-5-ylsulfanyl)-acetic acid OH Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 3 trifluoromethyl-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid 15 tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.50-6.17 (m, 5H, with the following distinct signal; 7.40 (s, 1 H), 4.59 (s, 2H), 3.99-3.85 (m, 1 H), 3.60-3.55 (m, 2H), 3.55-3.45 (m, 4H with the following distinct signal; 3.49 (s, 2H), 1.72-1.63 (m, 2H), 1.63-1.45 (m, 4H), 1.39-1.22 (m, 1 H), 1.10 0.95 (m, 2H), 0.78 (d, 3H) 20 HPLC-MS: m/z = 548 Example 130 {2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid F OH 25 WO 2007/006814 PCT/EP2006/064289 145 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-fluoro benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.48-7.30 (m, 3H, with the following distinct signal; 7.40 (s, 1 H)), 7.21-7.13 (m, 2H), 4.58 (s, 2H), 3.98-3.83 (m, 1 H), 3.60-3.54 (m, 4H, with the following distinct signal 3.49 (s, 2H)), 1.72-1.63 (m, 2H), 1.62-1.38 (m, 4H), 1.38-1.20 (m, 1 H), 1.10 0.94 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 482 10 Example 131 {2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid ci OH O" -. N N OH0 H 15 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-chloro benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, , DMSO-d) 8 7.52-7.49(m, 1 H), 7.47-7.41 (m, 1 H), 7.40 (s, 1 H), 7.34 20 7.28 (m, 2H), 4.60 (s, 2H), 4.00-3.87 (m, 1 H), 3.64-3.58 (m, 2H), 3.50-3.50 (m, 2H), 3.49 (s, 2H), 1.73-1.46 (m, 6H), 1.40-1.20 (m, 1H), 1.12-0.95 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 499 Example 132 25 {2-[3-[2-(2,3-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F OH N N , AZKS o WO 2007/006814 PCT/EP2006/064289 146 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2,3 difluoro-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.42-7.12 (m, 4H), 4.62 (s, 2H), 3.98-3.85 (m, 1 H), 3.62-3.30 (m, 6H ) with the following distinct signal: 3.47 (s)), 1.73-1.62 (m, 2H), 1.62-1.20 (m, 5H), 1.12-0.95 (m, 2H), 0.88 (d, 3H) HPLC-MS: m/z = 500 10 Example 133 {2-[3-[2-(2,6-Difluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F OH Y- O"-N \ N H F Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) 15 ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2,6 difluoro-benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 500 20 Example 134 {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid OH O N N OO H 4-Trans-methyl-cyclohexylamine (6.65 g, 44.4 mmol) and potassium carbonate (12.3 g, 88.8 25 mmol) in acetonitrile (50 mL) was heated to reflux before a solution of (3-bromo propoxymethyl)-benzene (10.2 g, 44.4 mmol) in acetonitrile (25 mL) over a period of 30 min. The reaction mixture was refluxed for 2 hours before the solvent was removed in vacuo. The residue was divided between diethyl ether (100 mL) and aqueous sodium hydroxide (1 N, 50 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue WO 2007/006814 PCT/EP2006/064289 147 was purified using column chromatography (SiO 2 , heptane-ethyl acetate 1:1) to give 8.4 g (3 benzyloxy-propyl)-(4-methyl-cyclohexyl)-amine. To this was added a solution of bis-tert-butyl dicarbonate (32 mmol, 1 N in THF) and the reaction mixture was stirred at room temperature for 18 hours before the solvent was removed in vacuo. The residue was dissolved in diethyl 5 ether (150 mL) and washed with water (2 x 100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 0.6 g of (3-benzyloxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester. This was subsequently dissolved ethanol (100 mL) and Pd/C (10%, 1 g) was added. The reaction mixture was stirred under H 2 (1 atm) for 4 hours. The reaction mixture was filtered throught a pad of celite and concentrated in vacuo to 10 give 7.9 g of (3-hydroxy-propyl)-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester. 2-Methyl-phenol (147 mg, 1.36 mmol), triphenylphoshine polystyrene (0.67 g, 3 mmol/g) and diethyl azadicarboxylate (DEAD) (261 mg, 1.5 mmol) in THF was stirred at room temperature for 16 hours before the solid was filtered off. Trifluoro acetic acid (1.5 mL) was added and the 15 reaction mixture was stirred for 1 hour before sodium hydroxide (10%, 5 mL) was added. The mixture was extracted with diethyl ether (3 x 5 mL), the organic phase dried over MgSO 4 , fil tered and the solvent was removed in vacuo to give (4-trans-methyl-cyclohexyl)-(3-o-tolyloxy propyl)-amine 20 {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy-propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid was prepared from (4-trans-methyl-cyclohexyl)-(3-o-tolyloxy-propyl)-amine and (2 amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester using the procedure described for the syn thesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid. HPLC-MS: m/z = 478 25 Example 135 {2-[3-[3-(4-Methoxy-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid I 0 ,N OH a O"-N' N OOH b H 30 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl- WO 2007/006814 PCT/EP2006/064289 148 cyclohexyl)-carbamic acid tert-butyl ester, 4-methoxy-phenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 494 5 Example 136 {2-[3-[3-(4-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid F O N N OH ON NK>S S 0 0H Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy 10 propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 4-fluoro-phenol and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. HPLC-MS: m/z = 482 15 Example 137 {2-[3-[3-(Indan-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid OH 0 N SOC NN N S OO bH Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy 20 propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, indane-5-ol and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. HPLC-MS: m/z = 504 25 Example 138 {2-[3-[3-(3,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid WO 2007/006814 PCT/EP2006/064289 149 F OHN N F~O --- N N OOH b H Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 3,4-difluorophenol and (2-amino-thiazol-5 5 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 500 Example 139 {2-[3-[3-(2,4-Difluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 10 ylsulfanyl}-acetic acid F_ F F OH O N NS 0 b H Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 2,4-difluorophenol and (2-amino-thiazol-5 15 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 500 Example 140 {2-[3-[3-(4-tert-Butyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 20 ylsulfanyl}-acetic acid 0 OH _a O ___N N OO b H Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 4-tert-butylphenol and (2-amino-thiazol-5 25 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 520 WO 2007/006814 PCT/EP2006/064289 150 Example 141 {2-[3-[3-(4-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid O NOH __ O___N N S b H 5 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 4-iso-propylphenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 10 HPLC-MS: m/z = 506 Example 142 {2-[3-[3-(3-Acetylamino-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol 5-ylsulfanyl}-acetic acid HN 0 N N OOH H 15 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 3-acetylaminophenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 20 HPLC-MS: m/z = 521 Example 143 {2-[3-[3-(2-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid OH N S OO 2H 25 WO 2007/006814 PCT/EP2006/064289 151 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 2-fluorophenol and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 5 'H NMR (400 MHz, DMSO-d) 8 7.42 (bs, 1 H), 7.25-7.09 (m, 3H), 6.97-6.90 (m, 1 H), 4.09 (t, 2H), 4.05-3.93 (m, 1 H), 3.48 (s, 2H), 3.42-3.32 (m, 2H), 2.02-1.90 (m, 2H), 1.73-1.44 (m, 6H), 1.35-1.21 (m, 1 H), 1.12-0.97 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 482 10 Example 144 {2-[3-[3-(3-Isopropyl-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-th iazol-5 ylsulfanyl}-acetic acid OH 0 N S />-S 0 N N O 0bH Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy 15 propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 2-iso-propoxyphenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 506 20 Example 145 {2-[3-[3-(Benzo[1,3]dioxol-5-yloxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid 0 OH O N O I 0'--'-N N S H Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy 25 propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, benzo[1,3]dioxol-5-ol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 508 WO 2007/006814 PCT/EP2006/064289 152 Example 146 (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(4-trifluoromethoxy-phenoxy)-propyl]-ureido} thiazol-5-ylsulfanyl)-acetic acid F N N S OOH H 5 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 4-trifluoromethoxyphenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 10 HPLC-MS: m/z = 548 Example 147 (2-{3-(4-trans-methyl-cyclohexyl)-3-[3-(3-trifluoromethoxy-phenoxy)-propyl]-ureido} thiazol-5-ylsulfanyl)-acetic acid F O F sOH O -N N S O H 15 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 3-trifluoromethoxyphenol and (2-amino-thiazol-5 ylsulfanyl)-acetic acid ethyl ester. 20 HPLC-MS: m/z = 548 Example 148 {2-[3-[3-(3-Fluoro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazo-5 ylsulfanyl}-acetic acid F OH ON N OOH H 25 WO 2007/006814 PCT/EP2006/064289 153 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 3-fluorophenol and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 5 HPLC-MS: m/z = 482 Example 149 3-{2-[3-[3-(2-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid 0 10 ' < OH o N N' ~H 10 Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy propyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 2-chlorophenol and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester. 15 'H NMR (400 MHz, DMSO-d) 8 7.43 (dd, 1H), 7.40 (s, 1H), 7.33-7.27 (m, 1H), 7.17-7.13 (m, 1H), 6.98-6.93 (m, 1H), 4.10 (t, 2H), 4.07-3.96 (m, 1H), 3.45-3.38 (m, 2H), 2.84 (t, 2H), 2.49 (t, 2H), 2.02-1.93 (m, 2H), 1.71-1.46 (6H), 1.35-1.25 (m, 1H), 1.11-0.97 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 512 20 Example 150 3-{2-[3-[3-(4-Chloro-phenoxy)-propyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid 0 ci OH a O-"" NN S yH Prepared as described for the synthesis of {2-[3-(4-trans-methyl-cyclohexyl)-3-(3-o-tolyloxy 25 propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using (3-hydroxy-propyl)-(4-methyl cyclohexyl)-carbamic acid tert-butyl ester, 4-chlorophenol and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 154 'H NMR (400 MHz, DMSO-d) 8 7.40 (s, 1 H), 7.32 (d, 2H)), 6.98 (d, 2H), 4.01 (t, 2H), 4.00 3.93 (m, 1 H), 3.47-3.27 (m, 2H), 2.84 (t, 2H), 2.49 (t, 2H), 1.99-1.87 (m, 2H), 1.73-1.42 (m, 6H), 1.38-1.22 (1H), 1.12-0.96 (m, 2H), 0.87 (d, 3H) HPLC-MS: m/z = 512 5 Example 151 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid COH F F N N S &u H 10 (General procedure (A) and (B)) Preparation of secondary amine: Preparation of cyclopentylmethyl-(3,4-difluoro-phenyl)-amine3,4-Difluoroaniline (18,5 mmol) dissolved in 50 ml of THF:MeOH (1:1) was added cyclopentanecarbaldehyde (20,4 mmol) 15 and 3A molsieves (5 g) and stirred for 0,5h at RT. Then NaBH 3 CN (37,1 mmol = 2 eqv.) was added and the reaction mixture was stirred for 13H at room temperature before it was filtered and the filtrate was concentrated in vacuo to give crude cyclopentylmethyl-(3,4-difluoro phenyl)-amine. 20 Coupling: To a solution of (2-amino-thiazol-4-yl)-acetic acid ethyl ester (1.0 mmol) and cyclopentylmethyl-(3,4-difluoro-phenyl)-amine (1.0 mmol) in dry toluene (10 mL) was added CDI (1.5 mmol) and DMAP (0.05 mmol). The mixture was stirred at 60 0C for 3H an then evaporated to dryness in vacuo. The crude product was purified on silica gel (gradient, from 25 heptane:ethyl acetate (10:1) to heptane:ethyl acetate (3:1)) to give {2-[3-cyclopentylmethyl-3 (3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester. Hydrolysis: {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl es 30 ter.(0.5 mmol) was dissolved in dioxane (2 mL) and treated with 1 N NaOH (2 mL) for 1 H at room temperature. Dioxane was removed by evaporation. Addition of 1 N HCI to pH 1 caused WO 2007/006814 PCT/EP2006/064289 155 precipitation. The precipitate was isolated by filtration, washed with water and dried to give the title compound as crystals. 'H NMR (400 MHz, DMSO-d) 8 7.42-7.53 (m, 1H), 7.11-7.22 (m, 1H), 6.75 (s, 1H), 3.67 (d, 1 H), 3.50 (s, 1H), 1.87-2.01 (m, 1H), 1.51-1.65 (m, 3H), 1.39-1.50 (m, 1H), 1.11-1.21 (m, 1H) 5 HPLC-MS: m/z = 396, Rt= 1.9 min Example 152 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid F OH F 1 N N S O &u H 10 Preparation of (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester: 5-Bromo-2-aminothiazole (25 g, 96 mmol) and K 2

CO

3 (26.5 g, 192 mmol) was suspended in DMF (50 mL) and stirred to 0 0C. Ethyl thioglycolate (11.6 mL, 96 mmol) was added during 10 min. The reaction mixture was allowed to reach room temperature and stirred for further 13H. Addition of water (100 mL) and EtOAc (150 mL). Separation of the organic phase fol 15 lowed by extraction of the aqueous phase with EtOAc (2x1 00 mL).The combined organic phases were washed with aqueous NaHCO3 (2000 mL), brine (2x200 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and purified by flash chromathography (ISCO 330 g silica column, eluent A: heptane / B: 2% TEA in EtOAc. Gradient from 30% B ->100% B.) to give 50-65% pure (2-aminothiazol 20 5-ylsulfanyl) acetic acid ethyl ester as a dark red-brown oil. 'H NMR (CDC1 3 ): 87.16 (s, 1H), 5.45 (bs, 2H), 4.26 (q, 2H), 3.39 (s, 2H), 1.28 (t, 3H). The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis 25 of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4 difluoroaniline, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.44-7.55 (m, 1 H), 7.38 (s, 1 H), 7.14-7.23 (m, 1 H), 3.68 (d, 1H), 3.47-3.53 (m, 1H), 1.88-1.99 (m, 1H), 1.53-1.64 (m, 3H), 1.41-1.50 (m, 1H), 1.12-1.21 30 (m, 1 H) HPLC-MS: m/z = 428, Rt= 2.5 min WO 2007/006814 PCT/EP2006/064289 156 Example 153 2-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2 methyl-propionic acid F OH F N N S 5 H Preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester: Step 1: 2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol) in MeOH (400 mL) was stirred at -10 C. Bromine (18.0 mL, 350 mmol) dissolved in MeOH (100 mL) satu 10 rated with with NaBr was slowly added keeping the internal temperature between -10 and 0 *C. After the addition the mixture was stirred at 0 0C for 3H and the reaction mixture was poured into ice water (1500 mL). Aqueous NH 4 0H was added to pH ca 8.5 causing precipita tion of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55%) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals. 15 Step 2: In a nitrogen atmosphere 5-thiocyanato-thiazol-2-ylamine (10 g, 64 mmol) dissolved in MeOH (300 mL) was added 2,3-dihydroxy-1,4-dithiolbutane (DTT, 9.8 g, 64 mmol) and stirred at room temperature for 11/2 h. Then 2-bromo-2-methyl-propionic acid ethyl ester (13.6 g, 70 mmol) and K 2

CO

3 (10.5 g, 76 mmol) was added and the reaction mixture was stirred for 20 further 13H. Addition of water (500 mL) and EtOAc (500 mL). Separation of the organic phase followed by extraction of the aqueous phase with EtOAc (2x300 mL). The combined organic phases were washed with water (500 mL) and brine (2x400 mL) and dried (MgSO4), filtered and evaporated. The crude product was dissolved in a small amount of DCM and pu rified by flash chromathography (heptane/EtOAc 2:1 -> 1:2). Fractions containing the product 25 were pooled and evaporated to a product containing impurities of DDT. This product was dis solved in diethyl ether (100 mL) and washed with water several times. The ether phase was dried (MgSO4), filtered and evaporated to give 8.45 g (54%) of 95% pure 2-(2-amino-thiazol 5-ylsulfanyl)-2-methyl-propionic acid ethyl ester as light brown crystals. 30 The title compound was prepared via 2-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol- WO 2007/006814 PCT/EP2006/064289 157 4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 2-(2-amino-thiazol 5-ylsulfanyl)-2-methyl-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.46-7.57 (m, 1H), 7.37 (s, 1H), 7.17-7.26 (m, 1H), 3.68 (d, 1 H), 1.88-1.99 (m, 1H), 1.53-1.64 (m, 3H), 1.41-1.49 (m, 1H), 1.39 (s, 3H), 1.12-1.21 (m, 1H) 5 HPLC-MS: m/z = 456, Rt= 2.2 min Example 154 2-({2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-methyl amino)-N,N-diethyl-acetamide F \ N F N N S 0 10 H Preparation of 2-[(2-Amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl-acetamide: A mixture of N,N-diethyl-2-methylamino-acetamide (12 mmol), 2-acetylamino-thiazole-5 sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (15 mmol) in DCM (50 mL) was stirred at room temperature over night. The reaction 15 mixture was diluted with DCM (50 mL) washed with 10% aq NaHSO4, water and brine, dried and concentrated to give 2-[(2-acetylamino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl acetamide (59%) as pale yellow crystals. This was suspended in EtOH (10 mL) and added 8N HCI in dioxane (10 mL) and heated for 3H at 80 0C and then cooled to room temperature and concentrated in vacuo to give 2-[(2-amino-thiazole-5-sulfonyl)-methyl-amino]-N,N 20 diethyl-acetamide as a hydrochloride as colourless crystals. The title compound was prepared as described for the synthesis of {2-[3-cyclopentylmethyl 3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 2-[(2-amino-thiazole-5-sulfonyl)-methyl-amino]-N,N-diethyl acetamide as a hydrochloride. 25 'H NMR (300 MHz, CDC1 3 ) 8 7.73 (s, 1 H), 7.28-7.39 (m, 1 H), 7.07-7.21 (m, 1 H), 3.95 (s, 1 H), 3.71 (d, 1 H), 3.30-3.43 (m, 3H), 2.91 (s, 3H), 1.98-2.11 (m, 1 H), 1.49-1.76 (m, 3H), 1.24-1.33 (m, 3H), 1.24 (t, 3H), 1.11 (t, 3H), 0.81-0.95 (m, 1H) HPLC-MS: m/z = 544, Rt= 2.2 min 30 Example 155 (S)-1-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyll pyrrolidine-2-carboxylic acid WO 2007/006814 PCT/EP2006/064289 158 F 0 N N N ' O OH F N N S 0 O &d H (General procedure (A), (B) and (H)) Step 1. A mixture of L-proline methylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5-sulfonyl 5 chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1 N HCI to pH 2. Isolation of the organic phase which was washed with water and brine, dried and concentrated to give (S)-1-(2-acetylamino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown crystals. These were suspended in EtOH (15 mL) and added 4N 10 HCI in dioxane (15 mL) and heated for 3H at 80 0C and then cooled to room temperature. Addition of aqueous NaHCO 3 to neutral pH. The organic phase was isolated and the aque ous phase was extracted with CH 2 Cl 2 , and the combined organic phases were dried and concentrated in vacuo to give (S)-1 -(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as colourless crystals. 15 The title compound was prepared via (S)-1 -{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl) ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic acid methyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol 4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and (S)-1 -(2-amino thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 20 1 H NMR (400 MHz, DMSO-d) 8 7.92 (s, 1H), 7.48-7.60 (m, 1H), 7.19-7.29 (m, 1H), 3.99-4.09 (m, 1H), 3.69 (d, 1H), 3.38-3.46 (m, 1H), 3.17-3.25 (m, 1H), 1.80-2.06 (m, 3H), 1.52-1.72 (m, 3H), 1.42-1.50 (m, 1H), 1.11-1.22 (m, 1H) HPLC-MS: m/z = 515, Rt= 2.1 min 25 Example 156 {2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylaminol acetic acid 0 F H OH F N N 5, &

H

WO 2007/006814 PCT/EP2006/064289 159 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido] thiazole-5-sulfonylamino}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and (2-amino-thiazole-5-sulfonylamino) 5 acetic acid ethyl ester the latter prepared in a similar manner as (S)-1 -(2-amino-thiazole-5 sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 'H NMR (400 MHz, DMSO-d) 8 8.25 (t, 1H), 7.76 (s, 1H), 7.48-7.59 (m, 1H), 7.16-7.27 (m, 1 H), 3.69 (d, 1 H), 3.63 (d, 1 H), 1.87-2.00 (m, 1 H), 1.53-1.65 (m, 3H), 1.40-1.51 (m, 1 H), 1.12-1.23 (m, 1 H) 10 HPLC-MS: m/z = 475, Rt= 1.9 min Example 157 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylaminol propionic acid 0 Fa H F N N S 0 15 H The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl) ureido]-thiazole-5-sulfonylamino}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 3-(2-amino-thiazole-5 20 sulfonylamino)-propionic acid ethyl ester the latter prepared in a similar manner as (S)-1 -(2 amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.84 (t, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.49 (dd, 1H), 7.19 7.25 (m, 1 H), 3.69 (d, 1 H), 2.97-3.04 (m, 1 H), 2.41 (t, 1 H), 1.89-1.99 (m, 1 H), 1.54-1.65 (m, 3H), 1.41 -1.50 (m, 1 H), 1.12-1.21 (m, 1 H) 25 HPLC-MS: m/z = 489, Rt= 1.9 min Example 158 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid WO 2007/006814 PCT/EP2006/064289 160 OH C ' '0 H C'S N N S C? H (General procedure (C) and (A)) Preparation of secondary amine: Preparation of cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amineStep 1: 5 4-(Methanesulonyl)aniline hydrochloride (19 mmol) suspended in 25 mL of Et20 was added Et3N (48 mmol) and then a solution cyclopentanecarbonyl chloride (19 mmol) in 25 mL of Et20 was added dropwise during in 10 min. The reaction mixture was stirred for 3h at RT and then diluted with EtOAc (100 mL) washed with 1 N aq HCI, water and aq sat NaHCO 3 . The organic phase was dried and concentrated in vacuo to give crude cyclopentanecarbox 10 ylic acid (4-methanesulfonyl-phenyl)-amide which was used without further purification. Step 2: In a nitrogen atmosphere a solution of cyclopentanecarboxylic acid (4-methanesulfonyl phenyl)-amide (10 mmol) in THF (20 mL) was added a solution of 1 M BH3 in THF (20 mL). The mixture was refluxed for 3H and cooled to RT. Addition of 10 mL of MeOH followed by 15 reflux for 15 min. The mixture was cooled and added water (100 mL)and EtOAc (200 mL). The organic phase was isolated and washed with 1 N NaOH, water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford cyclopentylmethyl-(4-methanesulfonyl phenyl)-amine as a yellow solid. 20 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl) ureido]-thiazol-4-yl}-acetic acid ethyl ester employing the coupling and hydrolysis protocol used for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl} acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazol 4-yl)-acetic acid ethyl ester. 25 'H NMR (400 MHz, DMSO-d) 8 7.93 (s, 1 H), 7.58 (d, 1 H), 6.76 (s, 1 H), 3.81 (d, 1 H), 3.51 (s, 1 H), 3.25 (s, 3H), 1.91-2.01 (m, 1H), 1.51-1.62 (m, 3H), 1.39-1.49 (m, 1H), 1.11-1.23 (m, 1H) HPLC-MS: m/z = 438, Rt= 1.6 min Example 159 30 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid WO 2007/006814 PCT/EP2006/064289 161

H

3 C ' N N \ S H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 5 acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.93 (d, 1 H), 7.58 (d, 1 H), 7.39 (s, 1 H), 3.81 (d, 1 H), 3.51 (s, 1 H), 3.26 (s, 3H), 1.90-2.01 (m, 1 H), 1.52-1.62 (m, 3H), 1.40-1.49 (m, 1 H), 1.13-1.23 (m, 1 H) HPLC-MS: m/z = 470, Rt= 1.7 min 10 Example 160 2-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-2 methyl-propionic acid O.0 0 N N 0 15 The title compound was prepared via 2-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl phenyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 2-(2 amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester. 20 'H NMR (400 MHz, DMSO-d) 8 7.94 (d, 1 H), 7.59 (d, 1 H), 7.38 (s, 1 H), 3.81 (d, 1 H), 3.26 (s, 3H), 1.90-2.01 (m, 1H), 1.52-1.63 (m, 3H), 1.40 (s, 3H), 1.37-1.48 (m, 1H), 1.13-1.24 (m, 1H) HPLC-MS: m/z = 498, Rt= 1.9 min Example 161 25 (S)-1-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 sulfonyl}-pyrrolidine-2-carboxylic acid WO 2007/006814 PCT/EP2006/064289 162 o, ,,o

H

3 C s 11OH N\ __ OH N N S 0 0 H The title compound was prepared via (S)-1 -{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic acid methyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl 5 phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl) amine and (S)-1 -(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.95 (d, 1 H), 7.92 (s, 1 H), 7.62 (d, 1 H), 4.04 (dd, 1 H), 3.82 (d, 1H), 3.37-3.46 (m, 1H), 3.26-3.28 (m, 3H), 3.18-3.25 (m, 1H), 1.80-2.08 (m, 3H), 1.65 1.76 (m, 1H), 1.52-1.64 (m, 3H), 1.40-1.50 (m, 1H), 1.12-1.23 (m, 1H) 10 HPLC-MS: m/z = 557, Rt= 1.8 min Example 162 {2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 sulfonylamino}-acetic acid 0 Is H OH

H

3 C' N o'H 15 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl) ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl} acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino 20 thiazole-5-sulfonylamino)-acetic acid ethyl ester the latter prepared in a similar manner as (S)-1 -(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.95 (d, 1 H), 7.76 (s, 1 H), 7.61 (d, 1 H), 3.82 (d, 1 H), 3.63 (s, 1H), 3.27 (s, 3H), 1.89-2.02 (m, 1H), 1.52-1.63 (m, 3H), 1.40-1.49 (m, 1H), 1.13-1.24 (m, 1H) HPLC-MS: m/z = 517, Rt= 1.6 min 25 Example 163 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5 sulfonylamino}-propionic acid WO 2007/006814 PCT/EP2006/064289 163 0, S,0 H 0

H

3 C' N N S OH & H The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl phenyl)-ureido]-thiazole-5-sulfonylamino}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] 5 th iazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 3-(2 amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester the latter prepared in a similar manner as (S)-1 -(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester. 'H NMR (400 MHz, DMSO-d) 8 7.95 (d, 1 H), 7.86 (t, 1 H), 7.78 (s, 1 H), 7.62 (d, 1 H), 3.82 (d, 1 H), 3.27 (s, 3H), 2.97-3.05 (m, 1 H), 2.41 (t, 1 H), 1.89-2.03 (m, 1 H), 1.52-1.63 (m, 3H), 1.39 10 1.49 (m, 1 H), 1.13-1.24 (m, 1 H) HPLC-MS: m/z = 531, Rt= 1.6 min Example 164 3-{2-[3-Cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll 15 propionic acid F 0 F F OH N N S H Preparation of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester: 5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K 2

CO

3 (26.5 g, 192 mmol) and the mixture was purged with N 2 for 5 min. The mixture was cooled to 00C on an 20 ice bath before 3-mercaptopropionic acid ethyl ester (12.9 g, 96 mmol) was added dropwise over the course of 30 min. The reaction mixture was stirred for 13Hours before water (400 mL) was added. The aquous mixture was extracted with Et 2 0 (1 x 500 mL, 2 x 250 mL). The combined organic phases was washed with saturated NH 4 CI (3 x 150 mL), dried (MgSO4). The solvent was removed in vacuo to give a dark residue which was purified by column 25 chromatography (SiO 2 , EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 g (49%) of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 8 7.1 (s, 1 H), 5.2 (bs, 2H), 4.2 (q, 2H), 2.8 (t, 2H), 2.6 (t, 2H), 1.3 (t, 3H).

WO 2007/006814 PCT/EP2006/064289 164 The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 3-(2-amino-thiazol-5-ylsulfanyl) 5 propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 7.43-7.55 (m, 1H), 7.37 (s, 1H), 7.15-7.22 (m, 1H), 3.68 (d, 1 H), 2.85 (t, 1 H), 2.46-2.50 (m, 1 H), 1.88-1.99 (m, 1 H), 1.53-1.64 (m, 3H), 1.41-1.50 (m, 1 H), 1.11-1.21 (m, 1H) HPLC-MS: m/z = 422, Rt= 2.1 min 10 Example 165 3-{2-[3-Cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyll propionic acid 0 s OH

H

3 C N N &4 H 15 The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and 3-(2 amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. 20 'H NMR (400 MHz, DMSO-d) 8 7.93 (d, 1 H), 7.58 (d, 1 H), 7.37 (s, 1 H), 3.81 (d, 1 H), 3.26 (s, 3H), 2.86 (t, 1 H), 2.47-2.50 (m, 1 H), 1.90-2.01 (m, 1 H), 1.52-1.62 (m, 3H), 1.40-1.49 (m, 1 H), 1.12-1.23 (m, 1 H) HPLC-MS: m/z = 484, Rt= 1.8 min 25 Example 166 {2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 165 O

H

3 C NH OH N N -- \ O_ H The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, 5 using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 ppm 10.06 (s, 1 H), 7.58 (d, 1 H), 7.47-7.51 (m, 1 H), 7.37 (d, 1 H), 7.32 (d, 1 H), 6.97 (d, 1 H), 3.66 (d, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 1.91-2.01 (m, 1 H), 1.53-1.64 (m, 3H), 1.41 -1.50 (m, 1 H), 1.14-1.24 (m, 1 H) 10 HPLC-MS: m/z = 449, Rt= 1.7 min Example 167 3-{2-[3-(3-Acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} propionic acid O

H

3 C NH OH N NS S 15 H The title compound was prepared via 3-{2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and 3-(2-amino-thiazol-5 20 ylsulfanyl)-propionic acid ethyl ester. 'H NMR (400 MHz, DMSO-d) 8 ppm 10.07 (s, 1 H), 7.57 (d, 1 H), 7.50 (s, 1 H), 7.30-7.37 (m, 1 H), 6.97 (d, 1 H), 3.66 (d, 1 H), 2.85 (t, 1 H), 2.47-2.50 (m, 1 H), 2.04 (s, 3H), 1.92-2.01 (m, 1 H), 1.53-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.14-1.24 (m, 1 H) HPLC-MS: m/z = 463, Rt= 1.8 min 25 Example 168 WO 2007/006814 PCT/EP2006/064289 166 {2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid 0 OH N N SO H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl 5 phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4 yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2-amino thiazol-5-ylsulfanyl) acetic acid ethyl ester 'H NMR (400 MHz, DMSO-d) 6 ppm 7.48 (s, 1 H), 7.27-7.42 (m, 3H), 3.65-3.77 (m, 1 H), 10 3.49 (s, 1 H), 2.97 (s, 3H), 1.87-2.00 (m, 1H), 1.51-1.62 (m, 3H), 1.40-1.48 (m, 1H), 1.12-1.23 (m, 1 H). HPLC-MS: M/Z = 463, Rt = 1,77 min. Example 169 15 3-{2-[3-Cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-propionic acid OH N N S H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as 20 described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2 amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester WO 2007/006814 PCT/EP2006/064289 167 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.44-7.51 (m, 1 H), 7.30-7.40 (m, 3H), 3.72 (d, 1 H), 2.96 (s, 3H), 2.85 (t, 1 H), (2.46-2.55, m, 2H), 1.89-1.99 (m, 1 H), 1.51-1.62 (m, 3H), 1.36-1.49 (m, 1 H), 1.07-1.28 (m, 1 H). HPLC-MS: M/Z = 477, Rt = 1,82 min 5 Example 170 {2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid

H

2 N 0 OH N N N 0 H 10 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-benzamide and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 15 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.05 (s, 1 H), 7.79-7.85 (m, 1 H), 7.43-7.52 (m, 3H), 7.38 (s, 1 H), 3.73 (d, 1 H), (3.33-3.4 m,2H), 3.49 (s, 1 H), 1.89-1.99 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.49 (m, 1 H), 1.13-1.24 (m, 1 H). HPLC-MS: M/Z = 435, Rt = 1,65 min 20 Example 171 3-{2-[3-(3-Carbamoyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll propionic acid H2N 0 OH N N S & H 25 WO 2007/006814 PCT/EP2006/064289 168 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-benzamide and (2-amino-thiazol-5-ylsulfanyl) 5 propionic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.04 (s, 1 H), 7.77-7.87 (m, 1 H), 7.41-7.52 (m, 3H), 7.35 (s, 1 H), 3.73 (d, 1 H), 2.85 (t, 1 H), (2.45-2.55, m, 2H), 1.88-2.01 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.09-1.27 (m, 1 H). HPLC-MS: M/Z = 449, Rt = 1,71 min., 10 Example 172 {2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid HN 0 OH N N IN S 0 H 15 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 20 1 H NMR (400 MHz, DMSO-d 6 ) 6 ppm 8.49 (d, 1 H), 7.77-7.81 (m, 1 H), 7.75 (s, 1 H), 7.42 7.53 (m, 1 H), 7.37 (s, 1 H), 3.73 (d, 1 H), 3.49 (s, 1 H), 2.79 (d, 3H), 1.88-1.98 (m, 1 H), 1.52 1.63 (m, 3H), 1.39-1.49 (m, 1 H), 1.11-1.23 (m, 1 H). HPLC-MS: M/Z = 449, Rt = 1,71 min 25 Example 173 3-{2-[3-Cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} propionic acid WO 2007/006814 PCT/EP2006/064289 169 HN 0 OH N N H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the 5 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and (2-amino-thiazol-5 ylsulfanyl) propionic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.47-8.53 (m, 1 H), 7.77-7.83 (m, 1 H), 7.75-7.77 (m, 1 H), 7.42-7.54 (m, 1 H), 7.35 (s, 1 H), 3.73 (d, 1 H), 2.85 (t, 1 H), 2.79 (d, 3H), 2.46-2.50 (m, 10 2H), 1.89-1.98 (m, 1 H), 1.50-1.64 (m, 3H), 1.40-1.46 (m, 1 H), 1.09-1.25 (m, 1 H). HPLC-MS: M/Z = 463, Rt = 1,78 min Example 174 {2-[3-Cyclopentylmethyl-3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} 15 acetic acid F F F 0 0 N T S S OH H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 20 acid, using cyclopentylmethyl-(3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester HPLC-MS: M/Z = 460, 2,15 min. Example 175 WO 2007/006814 PCT/EP2006/064289 170 {2-[3-Cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid NH 0" _S OH N N S O H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-sulfamoyl-phenyl)-ureido] 5 thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-sulfamoyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.82 (d, 1 H), 7.50 (d, 1 H), 7.41 (s, 1 H), 7.36-7.40 (m, 10 1 H), 3.77 (d, 1 H), 3.49 (s, 1 H), 1.88-1.98 (m, 1 H), 1.51-1.62 (m, 3H), 1.39-1.50 (m, 1 H), 1.11-1.21 (m, 1 H). HPLC-MS: M/Z = 471, Rt = 1,63 min Example 176 15 {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F F F O N N \ H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-fluoro-3-trifluoromethyl phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described 20 for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4 yl}-acetic acid, using cyclopentylmethyl-(4-fluoro-3-trifluoromethyl-phenyl)-amine and (2 amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.73-7.77 (m, 1 H), 7.67-7.72 (m, 1 H), 7.55 (t, 1 H), 7.39 (s, 1 H), 3.71 (d, 1 H), 3.49 (s, 1 H), 1.88-1.99 (m, 1 H), 1.52-1.63 (m, 3H), 1.40-1.51 (m, 1 H), 25 1.11-1.21 (m, 1 H). HPLC-MS: M/Z = 478, Rt = 2,19 min WO 2007/006814 PCT/EP2006/064289 171 Example 177 {2-[3-Cyclopentylmethyl-3-(4-trifluoromethyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid FF F 0~i ? \ pi S OH N N s H 5 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 10 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.76 (d, 1 H), 7.54 (d, 1 H), 7.39 (s, 1 H), 3.78 (d, 1 H), 3.50 (s, 1H), 1.89-1.99 (m, 1H), 1.51-1.62 (m, 3H), 1.39-1.50 (m, 1H), 1.12-1.23 (m, 1H). HPLC-MS: M/Z = 457, Rt = 2,18 min., Example 178 15 {2-[3-Cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid F F F 0 N S OH H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-trifluoromethoxy-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the 20 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-trifluoromethoxy-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.37-7.46 (m, 3H), 3.71 (d, 1 H), 3.49 (s, 1 H), 1.88-1.98 (m, 1 H), 1.52-1.63 (m, 3H), 1.40-1.51 (m, 1 H), 1.12-1.22 (m, 1 H). 25 HPLC-MS: M/Z = 476, Rt = 2,16 min WO 2007/006814 PCT/EP2006/064289 172 Example 179 {2-[3-Cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid 0

IINH

2 N S OH H 5 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-sulfamoyl-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-sulfamoyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 10 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.68-7.76 (m, 1 H), 7.57-7.62 (m, 1 H), 7.50-7.55 (m, 1 H), 7.43 (s, 1 H), 7.39 (s, 1 H), 3.75 (d, 1 H), 3.50 (s, 1 H), 1.95 (s, 1 H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.13-1.23 (m, 1 H). HPLC-MS: M/Z = 471, Rt = 1,63 min 15 Example 180 [2-(3-Benzo[1,3]dioxol-5-yI-3-cyclopentylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid O 0 N jN OH H The title compound was prepared via [2-(3-benzo[1,3]dioxol-5-yl-3-cyclopentylmethyl-ureido) 20 thiazol-5-ylsulfanyl]-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.36 (s, 1 H), 6.91-6.96 (m, 1 H), 6.76 (dd, 1 H), 6.08 (s, 25 1 H), 3.60 (d, 1 H), 3.48 (s, 1 H), 1.89-2.00 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.13-1.24 (m, 1 H).

WO 2007/006814 PCT/EP2006/064289 173 HPLC-MS: M/Z = 436, Rt = 1,96 min. Example 181 {2-[3-Cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl)-ureido]-thiazol-5-ylsulfanyl} 5 acetic acid F F_ 0 F 0 N'iN ' OH H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-trifluoromethoxy-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 10 acid, using cyclopentylmethyl-(3-trifluoromethoxy-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.53 (t, 1 H), 7.39 (s, 1 H), 7.33-7.37 (m, 1 H), 7.30 (d, 1 H), 3.74 (d, 1 H), 3.50 (s, 1 H), 1.88-1.99 (m, 1 H), 1.51-1.62 (m, 3H), 1.39-1.50 (m, 1 H), 1.10-1.21 (m, 1 H). 15 HPLC-MS: M/Z = 476, Rt = 2,20 min Example 182 {2-[3-Cyclopentylmethyl-3-(6-methoxy-pyridin-3-yI)-ureido]-thiazol-5-ylsulfanyll-acetic acid N N O H O 20 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(6-methoxy-pyridin-3-yl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(6-methoxy-pyridin-3-yl)-amine and (2-amino-thiazol-5 25 ylsulfanyl) acetic acid ethyl ester WO 2007/006814 PCT/EP2006/064289 174 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.10 (d, 1 H), 7.65 (dd, 1 H), 7.37 (s, 1 H), 6.87 (d, 1 H), 3.88 (s, 3H), 3.64 (d, 1 H), 3.49 (s, 1 H), 1.87-2.00 (m, 1 H), 1.53-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.11-1.25 (m, 1 H). HPLC-MS: M/Z = 423, Rt = 1,83 min 5 Example 183 {2-[3-(6-Acetylamino-pyridin-3-yI)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid OOH N N S H 10 The title compound was prepared via {2-[3-(6-acetylamino-pyridin-3-yl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-[5-(cyclopentylmethyl-amino)-pyridin-2-yl]-acetamide and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 15 1H NMR (400 MHz, DMSO-d) 6 ppm 10.63 (s, 1H), 8.22 (d, 1H), 8.10 (d, 1H), 7.71 (dd, 1H), 7.38 (s, 1 H), 3.67 (d, 1H), 3.49 (s, 1H), 2.11 (s, 3H), 1.91-2.00 (m, 1H), 1.53-1.64 (m, 3H), 1.40-1.50 (m, 1 H), 1.12-1.22 (m, 1 H). HPLC-MS: M/Z = 450, Rt = 1,55 min 20 Example 184 {2-[3-(3-Acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid 0 YNH N OH H The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-pentyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3- WO 2007/006814 PCT/EP2006/064289 175 cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino phenyl)-acetamide, pentanal and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.05 (s, 1 H), 7.57 (d, 1 H), 7.50 (s, 1 H), 7.31-7.39 (m, 1 H), 6.95 (d, 1 H), 3.61-3.68 (m, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 1.41-1.49 (m, 1 H), 1.20-1.30 5 (m, 3H), 0.83 (t, 3H). HPLC-MS: M/Z = 437, Rt = 1,70 min Example 185 {2-[3-(3-Acetylamino-phenyl)-3-cyclohexylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic 10 acid 0 ANH N N -\ OH/-/ H The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclohexylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, 15 using N-(3-amino-phenyl)-acetamide, cyclohexylcarbaldehyde and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. HPLC-MS: M/Z = 463, Rt = 1,80 min Example 186 20 {2-[3-(3-Acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid 0 ANH L~* 0 N -\ s _ N N s OH H The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-(3-methyl-butyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3- WO 2007/006814 PCT/EP2006/064289 176 amino-phenyl)-acetamide, 3-methylbutanal and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.05 (s, 1 H), 7.57 (d, 1 H), 7.47 (s, 1 H), 7.31-7.38 (m, 1 H), 6.95 (d, 1 H), 3.64-3.72 (m, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 1.50-1.60 (m, 1 H), 1.31-1.39 5 (m, 1 H), 0.85 (d, 3H). HPLC-MS: M/Z = 437, Rt = 1,68 min Example 187 {2-[3-(3-Acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid 0 ANH 0 N S OH HO 10 The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3 cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino phenyl)-acetamide, hexanal and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 15 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.05 (s, 1 H), 7.57 (d, 1 H), 7.47 (s, 1 H), 7.30-7.39 (m, 1 H), 6.94 (d, 1 H), 3.59-3.69 (m, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 1.39-1.49 (m, 1 H), 1.19-1.29 (m, 3H), 0.80-0.87 (m, 3H). HPLC-MS: M/Z = 451, Rt = 1,83 min., 20 Example 188 {2-[3-(3-Acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid 0 ANH " 0 N -\ S-/ N N 4s S OH

H

WO 2007/006814 PCT/EP2006/064289 177 The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclopropylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopropanecarboxaldehyde and (2-amino-thiazol-5 5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.05 (s, 1 H), 7.58 (d, 1 H), 7.52 (s, 1 H), 7.30-7.39 (m, 1 H), 6.97 (d, 1 H), 3.55 (d, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 0.91-1.00 (m, 1 H), 0.36-0.42 (m, 1H), 0.09-0.15 (m, 1H). HPLC-MS: M/Z = 421, Rt = 1,47 min., 10 Example 189 {2-[3-(3-Acetylamino-phenyl)-3-(3,3-dimethyl-butyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid 0 ANH N** 0 N -\ s _ N N S OH H 15 The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-(3,3-dimethyl-butyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, 3,3-dimethylbutyraldehyde and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 20 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.05 (s, 1 H), 7.59 (d, 1 H), 7.45 (s, 1 H), 7.31-7.38 (m, 1 H), 6.95 (d, 1 H), 3.64-3.71 (m, 1 H), 3.49 (s, 1 H), 2.04 (s, 3H), 1.35-1.44 (m, 1 H), 0.87 (s, 9 H). HPLC-MS: M/Z = 451, Rt = 1,76 min 25 Example 190 {2-[3-Cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 178 F Fj: 0 S OH N N S H The title compound was prepared via {2-[3-cyclohexylmethyl-3-(3,4-difluoro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, 5 using cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.45-7.55 (m, 1 H), 7.38 (s, 1 H), 7.15-7.20 (m, 1 H), 3.58 (d, 1H), 3.49 (s, 1H), 1.54-1.69 (m, 3H), 1.35-1.46 (m, 1H), 1.05-1.13 (m, 3H), 0.86-0.97 (m, 1 H). 10 HPLC-MS: M/Z = 442, Rt = 2,16 min., Example 191 [2-(3-Benzo[1,3]dioxol-5-yI-3-cyclohexylmethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid O N N N S OH H 15 The title compound was prepared via [2-(3-benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido) thiazol-5-ylsulfanyl]-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 20 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.36 (s, 1 H), 6.93 (s, 1 H), 6.93 (d, 1 H), 6.76 (dd, 1 H), 6.08 (s, 1H), 3.51 (d, 1H), 3.48 (s, 1H), 1.55-1.72 (m, 3H), 1.35-1.46 (m, 1H), 1.06-1.17 (m, 3H), 0.87-0.97 (m, 1 H). HPLC-MS: M/Z = 450, Rt = 2,08 min 25 Example 192 {2-[3-Cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl)-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 179 0 N 0 --- , / ,2 N N S OH H The title compound was prepared via {2-[3-cyclohexylmethyl-3-(6-methoxy-pyridin-3-yl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 5 acid, using cyclohexylmethyl-(6-methoxy-pyridin-3-yl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.09 (d, 1 H), 7.64 (dd, 1 H), 7.37 (s, 1 H), 6.87 (d, 1 H), 3.88 (s, 3H), 3.54 (d, 1H), 3.49 (s, 1H), 1.55-1.71 (m, 3H), 1.34-1.45 (m, 1H), 1.06-1.17 (m, 3H), 0.86-0.97 (m, 1 H) 10 HPLC-MS: M/Z = 437, Rt = 1,96 min., Example 193 {2-[3-Cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid HN 0 0 k XIS OH N 'N S 15 H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-ethyl-benzamide and (2-amino-thiazol-5 20 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.53 (t, 1 H), 7.81 (d, 1 H), 7.77 (s, 1 H), 7.42-7.56 (m, 1 H), 7.37 (s, 1 H), 3.73 (d, 1 H), 3.49 (s, 1 H), 3.26-3.32 (m, 1 H), 1.88-1.99 (m, 1 H), 1.52-1.63 (m, 3H), 1.39-1.50 (m, 1H), 1.14-1.23 (m, 1H), 1.12 (t, 3H). HPLC-MS: M/Z = 463, Rt = 1,75 min. 25 WO 2007/006814 PCT/EP2006/064289 180 Example 194 {2-[3-Cyclobutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid F F OH H The title compound was prepared via {2-[3-cyclbutylmethyl-3-(3,4-difluoro-phenyl)-ureido] 5 thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclobutylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.42-7.51 (m, 1 H), 7.38 (s, 1 H), 7.10-7.16 (m, 1 H), 10 3.75 (d, 1 H), 3.49 (s, 1 H), 2.35-2.44 (m, 1 H), 1.83-1.92 (m, 1 H), 1.71-1.82 (m, 1 H), 1.55-1.65 (m, 1 H). HPLC-MS: M/Z = 414, Rt = 1,96 min Example 195 15 {2-[3-Cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid HN 0 0 'k 1 S OH N N' S OH The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isopropylcarbamoyl phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described 20 for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4 yl}-acetic acid, using 3-(cyclopentylethyl-amino)-N-isopropyl-benzamide and (2-amino thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 8.26 (d, 1 H), 7.78-7.88 (m, 1 H), 7.42-7.52 (m, 1 H), 7.37 (s, 1 H), 4.05-4.16 (m, 1 H), 3.73 (d, 1 H), 3.49 (s, 1 H), 1.88-2.00 (m, 1 H), 1.52-1.64 (m, 25 3H), 1.40-1.51 (m, 1H), 1.18-1.24 (m, 1H), 1.17 (d, 3H) HPLC-MS: M/Z = 477, Rt = 1,86 min., WO 2007/006814 PCT/EP2006/064289 181 Example 196 (2-{3-[3-(Azetidine-1-carbonyl)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5 ylsulfanyl)-acetic acid CN O N NN S OH 5 & H The title compound was prepared via (2-{3-[3-(azetidine-1 -carbonyl)-phenyl]-3 cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using azetidin-1 -yl-[3-(cyclopentylmethyl-amino)-phenyl]-methanone 10 and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.47-7.55 (m, 3H), 7.42-7.45 (m, 1 H), 7.37 (s, 1 H), 4.27-4.34 (t, 1 H), 4.04 (t, 1 H), 3.72 (d, 1 H), 3.50 (s, 1 H), 2.21-2.29 (m, 1 H), 1.89-1.97 (m, 1 H), 1.52-1.61 (m, 3H), 1.40-1.49 (m, 1 H), 1.12-1.21 (m, 1 H) HPLC-MS: M/Z = 475, Rt = 1,74 min 15 Example 197 {2-[3-(3,4-Difluoro-phenyl)-3-(4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyll acetic acid F F F N OH H 20 The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-methyl cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] thiazol-4-yl}-acetic acid, using 4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2 25 amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. HPLC-MS: M/Z = 456, Rt = 2,29 min WO 2007/006814 PCT/EP2006/064289 182 Example 198 {2-[3-(3,4-Difluoro-phenyl)-3-(4-trifluoromethyl-cyclohexylmethyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F 0 N S H F F_ 5 F The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-trifluoromethyl cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] thiazol-4-yl}-acetic acid, using 4-trifluoromethyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine 10 and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.51-7.58 (m, 1 H), 7.44-7.49 (m, 1 H), 7.38 (s, 1 H), 7.17-7.23 (m, 1 H), 3.78 (d, 1 H), 3.50 (s, 1 H), 2.18-2.30 (m, 1 H), 1.65-1.73 (m, 1 H), 1.39-1.64 (m, 8 H) HPLC-MS: M/Z = 510, Rt = 2,20 min 15 Example 199 {2-[3-(4-tert-Butyl-cyclohexylmethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F NN HH 20 The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(4-tert-butyl cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using 4-tert-butyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 25 HPLC-MS: M/Z = 498, Rt = 2,59 min.

WO 2007/006814 PCT/EP2006/064289 183 Example 200 {2-[3-Cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid F F F 0 F N N I S OH H 5 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 10 HPLC-MS: M/Z = 446, Rt = 2,59 min. Example 201 {2-[3-(3-Chloro-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid ci F OH F N N S O 15 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-chloro-4-fluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-4-fluoro-phenyl)-amine and (2-amino-thiazol-5 20 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.62 (dd, 1 H), 7.45 (t, 1 H), 7.38 (s, 1 H), 7.32-7.37 (m, 1 H), 3.68 (d, 1 H), 3.49 (s, 1 H), 1.93 (ddd, 1 H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.11 1.21 (m, 1 H) HPLC-MS: M/Z = 444, Rt = 2,28 min., 25 Example 202 {2-[3-Cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid WO 2007/006814 PCT/EP2006/064289 184 F F00 F N N S OH &' H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,4-difluoro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, 5 using cyclopentylmethyl-(2,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.45-7.52 (m, 1 H), 7.34-7.41 (m, 1 H), 7.14 (t, 1 H), 3.62 (d, 1H), 3.50 (s, 1H), 1.86-1.97 (m, 1H), 1.52-1.63 (m, 3H), 1.40-1.51 (m, 1H), 1.12-1.22 (m, 1 H) HPLC-MS: M/Z = 367, Rt = 2,14 min 10 Example 203 {2-[3-Cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid ci ci 0 0 N\ _/-'< S- OH N N S O H 15 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3-dichlorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 20 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.65 (dd, 1 H), 7.40-7.46 (m, 1 H), 7.36 (s, 1 H), 3.80 3.90 (m, 1 H), 3.50 (s, 1H), 1.97 (ddd, 1H), 1.51-1.70 (m, 3H), 1.41-1.51 (m, 1H), 1.12-1.27 (m, 1 H) HPLC-MS: M/Z = 460, Rt = 2,31 min. 25 Example 204 {2-[3-Cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll acetic acid WO 2007/006814 PCT/EP2006/064289 185 IF 0 0 NN S OH H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-fluoro-4-methoxy-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 5 acid, using cyclopentylmethyl-(3-fluoro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.37 (s, 1 H), 7.25 (dd, 1 H), 7.19 (t, 1 H), 7.09 (dd, 1 H), 3.87 (s, 3H), 3.63 (d, 1 H), 3.49 (s, 1 H), 1.87-1.97 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.50 (m, 1 H), 1.12-1.22 (m, 1 H) 10 HPLC-MS: M/Z = 304, Rt = 2,11 min., Example 205 {2-[3-(3-Acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid 0 YNH 0 ' ' ,IT 1 OH N N S H 15 The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-benzyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3 cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (3 acetylamino-phenyl)-benzylamine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.99 (s, 1 H), 7.53 (d, 1 H), 7.41 (s, 1 H), 7.39 (s, 20 1 H), 7.26-7.33 (m, 1 H), 7.20-7.26 (m, 3H), 6.88 (d, 1 H), 4.94 (s, 1 H), 3.51 (s, 1 H), 2.01 (s, 3H) HPLC-MS: M/Z = 457, Rt = 1.64 min., Example 206 25 {2-[3-(3-Acetylamino-phenyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyll-acetic acid WO 2007/006814 PCT/EP2006/064289 186 0 ANH 0 S 0 N _ /9 N S OH H The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-phenethyl-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, 5 using (3-acetylamino-phenyl)-phenethylamine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. HPLC-MS: M/Z = 471, Rt = 1.82 min. Example 207 10 {2-[3-(2-Cyclopentylethyl)-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid F F ~N Q N\s 0 F Nhi OH H The title compound was prepared via {2-[3-cyclopentylethyl-3-(3,4-difluoro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis 15 of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.43-7.54 (m, 1H), 7.38 (s, 1H), 7.13-7.19 (m, 1H), 3.63-3.73 (m, 1 H), 3.49 (s, 1 H), 1.66-1.76 (m, 3H), 1.51-1.56 (m, 1 H), 1.43-1.49 (m, 3H), 20 0.99-1.09 (m, 1 H) HPLC-MS: M/Z = 442, Rt = 2,31 min. Example 208 WO 2007/006814 PCT/EP2006/064289 187 {2-[3-(3,4-Difluoro-pheny)-3-( trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F F N N S OH H The title compound was prepared via {{2-[3-(3,4-difluoro-phenyl)-3-( trans-4-methyl 5 cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.45-7.55 (m, 1 H), 7.39 (s, 1 H), 7.15-7.21 (m, 1 H), 10 3.58 (d, 1H), 3.49 (s, 1H), 1.59-1.69 (m, 3H), 1.18-1.39 (m, 1H), 0.86-0.98 (m, 1H), 0.73-0.84 (m, 3H) HPLC-MS: M/Z = 456, Rt = 2,39 min Example 209 15 {2-[3-(3-Acetylamino-4-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid 0 YNH F) 'N N OH H The title compound was prepared via {2-[3-(3-acetylamino-4-fluoro-phenyl)-3 cyclopentylmethyl-u reido]-th iazol-5-ylsu Ifanyll-acetic acid ethyl ester in a similar manner as 20 described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol 4-yl}-acetic acid, using N-(3-amino-4-fluoro-phenyl)-acetamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) S ppm 9.85 (s, 1 H), 7.90 (d, 1 H), 7.37 (s, 1 H), 7.24-7.31 (m, 1 H), 7.02-7.08 (m, 1 H), 3.63 (d, 1 H), 3.49 (s, 1 H), 2.09 (s, 3H), 1.96 (ddd, 1 H), 1.52-1.65 (m, 25 3H), 1.40-1.51 (m, 1 H), 1.12-1.24 (m, 1 H) HPLC-MS: M/Z = 467, Rt = 1,74 min WO 2007/006814 PCT/EP2006/064289 188 Example 210 {2-[3-Cyclopentylmethyl-3-(3-propionylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid 0 NH 0 _ 0 N N N\ 5 H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-propionylamino-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-propionamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5 10 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.01 (s, 1 H), 7.60 (d, 1 H), 7.53 (s, 1 H), 7.37 (s, 1 H), 7.33 (t, 1 H), 6.96 (d, 1 H), 3.66 (d, 1 H), 3.50 (s, 1 H), 2.32 (q, 1 H), 1.91-2.01 (m, 1 H), 1.53 1.64 (m, 3H), 1.40-1.51 (m, 1H), 1.14-1.24 (m, 1H), 1.07 (t, 3H) HPLC-MS: M/Z = 463, Rt = 1,82 min. 15 Example 211 {2-[3-Cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid 0 NH O N 'N S S OH H 20 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isobuturylamino-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-isobutyramide, cyclopentanecarbaldehyde and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 189 1 H NMR (400 MHz, DMSO-d) d ppm 9.96 (s, 1 H), 7.62 (d, 1 H), 7.54 (s, 1 H), 7.37 (s, 1 H), 7.33 (t, 1 H), 6.96 (d, 1 H), 3.66 (d, 1 H), 3.49 (s, 1 H), 2.54-2.62 (m, 1 H), 1.91-2.03 (m, 1 H), 1.53-1.64 (m, 3H), 1.40-1.50 (m, 1H), 1.15-1.27 (m, 1H), 1.09 (d, 3H) HPLC-MS: M/Z = 477, Rt = 1,92 min. 5 Example 212 (2-{3-[3-(Cyclopentanecarbonyl-amino)-phenyl]-3-cyclopentylmethyl-ureido}-thiazol-5 ylsulfanyl)-acetic acid 0 NH N N S OH & H 10 The title compound was prepared via (2-{3-[3-(cyclopentanecarbonyl-amino)-phenyl]-3 cyclopentylmethyl-ureido}-thiazol-5-ylsulfanyl)-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol 4-yl}-acetic acid, using cyclopentanecarboxylic acid (3-amino-phenyl)-amide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 15 1 H NMR (400 MHz, DMSO-d) 6 ppm 10.00 (s, 1 H), 7.62 (d, 1 H), 7.54 (s, 1 H), 7.37 (s, 1 H), 7.33 (t, 1 H), 6.96 (d, 1 H), 3.66 (d, 1 H), 3.49 (s, 1 H), 2.77 (dq, 1 H), 1.91-2.02 (m, 1 H), 1.78 1.89 (m, 1 H), 1.65-1.71 (m, 3H), 1.53-1.62 (m, 3H), 1.40-1.49 (m, 1 H), 1.14-1.25 (m, 1 H) HPLC-MS: M/Z = 503, Rt = 2,09 min 20 Example 213 {2-[3-(trans-4-Methyl-cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F F 0 F N N S OH H The title compound was prepared via {2-[3-( trans-4-methyl-cyclohexylmethyl)-3-(2,3,4 25 trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]- WO 2007/006814 PCT/EP2006/064289 190 th iazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.31-7.43 (m, 3H), 3.55 (d, 1 H), 3.50 (s, 1 H), 1.65 (t, 3H), 1.20-1.38 (m, 1 H), 0.87-0.99 (m, 1 H), 0.83 (d, 3H), 0.74-0.86 (m, 1 H) 5 HPLC-MS: M/Z = 474, Rt = 2,41 min., Example 214 {2-[3-Cyclohexylmethyl-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid F F F 0 F N N S OH 10 H The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5 15 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.31-7.44 (m, 3H), 3.55 (d, 1 H), 3.50 (s, 1 H), 1.56-1.70 (m, 3H), 1.34-1.47 (m, 1 H), 1.06-1.20 (m, 3H), 0.85-1.00 (m, 1 H) HPLC-MS: M/Z = 460, Rt = 2,32 min., 20 Example 215 {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid F F 0 1-1 OH N N S O H The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(2,3-difluoro-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis 25 of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(2,3-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 191 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.35-7.46 (m, 1 H), 7.21-7.29 (m, 1 H), 3.68 (d, 1 H), 3.50 (s, 1 H), 1.89-2.00 (m, 1 H), 1.52-1.63 (m, 3H), 1.40-1.50 (m, 1 H), 1.09-1.24 (m, 1 H) HPLC-MS: M/Z = 427, Rt = 2,07 min 5 Example 216 {2-[3-Cyclopentylmethyl-3-(4-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid I0 U 0 N0 SNN NS S OH H The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(4-methoxy-phenyl)-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis 10 of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.36 (s, 1 H), 7.22 (d, 1 H), 6.98 (d, 1 H), 3.78 (s, 3H), 3.62 (d, 1 H), 3.49 (s, 1 H), 1.87-1.98 (m, 1 H), 1.52-1.64 (m, 3H), 1.39-1.50 (m, 1 H), 1.13-1.24 15 (m, 1 H) HPLC-MS: M/Z = 422, Rt = 2,03 min. Example 217 {2-[3-(3-Chloro-4-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} 20 acetic acid 0 0 N NI S O H H The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(3-chloro-4-methoxy phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4 25 yl}-acetic acid, using (methyl-cyclohexylmethyl-(3-chloro-4-methoxy-phenyl)-amine and (2 amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester.

WO 2007/006814 PCT/EP2006/064289 192 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.41 (d, 1 H), 7.37 (s, 1 H), 7.25 (dd, 1 H), 7.17 (d, 1 H), 3.88 (s, 3H), 3.63 (d, 1 H), 3.49 (s, 1 H), 1.87-1.98 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.51 (m, 1 H), 1.12-1.23 (m, 1 H) HPLC-MS: M/Z = 456, Rt = 2,16 min. 5 Example 218 {2-[3-Cyclopentylmethyl-3-(2,2-difluoro-benzo[1,3]dioxol-5-yI)-ureido]-thiazol-5 ylsulfanyl}-acetic acid F F 0 0 SN N S OH H 10 The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,2-difluoro benzo[1,3]dioxol-5-yl)-ureido]-thiazol-5-ylsulfanyll-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl) u reido]-th iazol-4-yl}-acetic acid, using 2,2-difluoro-benzo[1,3]dioxol-5-yl-cyclohexylmethyl amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 15 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.50 (d, 1 H), 7.44 (d, 1 H), 7.38 (s, 1 H), 7.15 (dd, 1 H), 3.66 (d, 1 H), 3.49 (s, 1 H), 1.89-1.99 (m, 1 H), 1.54-1.65 (m, 3H), 1.40-1.52 (m, 1 H), 1.13-1.23 (m, 1 H) HPLC-MS: M/Z = 472, Rt = 2,24 min. 20 Example 219 {2-[3-Cyclopentylmethyl-3-(3-methanesulfonylamino-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid HN' 0 Ik , ' S/ OH N N S H The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methanesulfonylamino 25 phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic WO 2007/006814 PCT/EP2006/064289 193 acid, using N-(3-Amino-phenyl)-methanesulfonamide, cyclopentanecarbaldehyde and (2 amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 9.84 (s, 1 H), 7.35-7.41 (m, 1 H), 7.11-7.18 (m, 1 H), 7.04 (d, 1 H), 3.65 (d, 1 H), 3.50 (s, 1 H), 3.04 (s, 3H), 1.91-2.02 (m, 1 H), 1.52-1.64 (m, 3H), 5 1.39-1.50 (m, 1 H), 1.13-1.24 (m, 1 H) HPLC-MS: M/Z = 485, Rt = 1,78 min Example 220 {2-[3-Cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic 10 acid F F N O S OH H F The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,4,6-trifluoro-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 15 acid, using cyclopentylmethyl-(2,4,6-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.31-7.41 (m, 3H), 3.35-3.61 (m, 3H), 1.89-1.99 (m, 1 H), 1.52-1.63 (m, 3H), 1.42-1.50 (m, 1 H), 1.13-1.24 (m, 1 H) HPLC-MS: M/Z = 446, Rt = 2,06 min 20 Example 221 {2-[3-(3-Chloro-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid ci F 0 IX O~SH N N S H 25 The title compound was prepared via {2-[3-(3-chloro-2-fluoro-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic WO 2007/006814 PCT/EP2006/064289 194 acid, using cyclopentylmethyl-(3-chloro-2-fluoro-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.53-7.62 (m, 1 H), 7.35-7.45 (m, 1 H), 7.27 (t, 1 H), 3.66 (d, 1 H), 3.51 (s, 1 H), 1.87-1.98 (m, 1 H), 1.52-1.64 (m, 3H), 1.42-1.50 (m, 1 H), 1.12-1.23 (m, 5 1 H) HPLC-MS: M/Z = 444, Rt = 2,11 min Example 222 {2-[3-Cyclopentylmethyl-3-(4-fluoro-3-methoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll 10 acetic acid F 1 N 7-' F N 'N S OH H The title compound was prepared via {2-[3-(4-fluoro-3-methoxy-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic 15 acid, using cyclopentylmethyl-(4-fluoro-3-methoxy-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) d ppm 7.38 (s, 1H), 7.24 (dd, 1H), 7.13 (dd, 1H), 6.84-6.90 (m, 1 H), 3.83 (s, 3H), 3.66 (d, 1 H), 3.49 (s, 1 H), 1.90-2.01 (m, 1 H), 1.54-1.65 (m, 3H), 1.40 1.51 (m, 1 H), 1.13-1.24 (m, 1 H) 20 HPLC-MS: M/Z = 440, Rt = 2,02 min. Example 223 {2-[3-Cyclopentylmethyl-3-(2,3-difluoro-4-methoxy-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid i F 0 F0 C11S OH N N' S 25 The title compound was prepared via {2-[3-(2,3-difluoro-4-methoxy-phenyl)-3 cyclopentylmethyl-u reido]-th iazol-5-ylsu Ifanyll-acetic acid ethyl ester in a similar manner as WO 2007/006814 PCT/EP2006/064289 195 described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3-difluoro-4-methoxy -phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.38 (s, 1 H), 7.17-7.25 (m, 1 H), 7.02-7.10 (m, 1 H), 5 3.91 (s, 3H), 3.61 (d, 1 H), 3.50 (s, 1 H), 1.88-1.98 (m, 1 H), 1.52-1.64 (m, 3H), 1.40-1.50 (m, 1 H), 1.13-1.23 (m, 1 H) HPLC-MS: M/Z = 458, Rt = 2,07 min. Example 224 10 {2-[3-Cyclopentylmethyl-3-(4-isopropoxy-phenyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid 0 0 HO N N S O &' H The title compound was prepared via {2-[3-(4-isopropoxy-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the 15 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-isopropoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.36 (s, 1 H), 7.19 (d, 1 H), 6.95 (d, 1 H), 4.57-4.66 (m, 1 H), 3.61 (d, 1 H), 3.49 (s, 1 H), 1.88-1.99 (m, 1 H), 1.51-1.65 (m, 3H), 1.39-1.50 (m, 1 H), 1.29 20 (d, 3H), 1.13-1.24 (m, 1H) HPLC-MS: M/Z = 450, Rt = 2,18 min. Example 225 {2-[3-Cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} 25 acetic acid F N N S OH The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-fluoro-2-methyl-phenyl) ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the WO 2007/006814 PCT/EP2006/064289 196 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-fluoro-2-methyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.36 (s, 1 H), 7.26 - 7.32 (m, 1 H), 7.14 - 7.22 (m, 1 H), 5 7.10 (d, 1 H), 3.74 - 3.86 (m, 1 H), 3.49 (s, 2 H), 3.35 - 3.43 (m, 1 H), 2.04 (d, 3 H), 1.92 - 2.01 (m, 1 H), 1.53 - 1.65 (m, 4 H), 1.41 - 1.51 (m, 2 H), 1.14 - 1.26 (m, 2 H) HPLC-MS: M/Z = 424, Rt = 2,10 min. Example 226 10 {2-[3-(3-Chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl} acetic acid CI CH, N N S & H The title compound was prepared via {2-[3-(3-chloro-2-methoxy-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the 15 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-methoxy-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester. 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.47-7.51 (m, 1 H), 7.37 (s, 1 H), 7.23-7.27 (m, 1 H), 7.16-7.20 (m, 1 H), 3.74 (s, 3H), 3.50 (s, 2H), 1.88-1.98 (m, 1H), 1.53-1.64 (m, 4H), 1.40-1.50 20 (m, 2H), 1.11-1.22 (m, 2H) HPLC-MS: M/Z = 456, Rt = 2,15 min. Example 227 {2-[3-(3-Chloro-2-methyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll 25 acetic acid CI CH, O SH 0 N N S O The title compound was prepared via {2-[3-(3-chloro-2-methyl-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the WO 2007/006814 PCT/EP2006/064289 197 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-methyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.45 (d, 1 H), 7.36 (s, 1 H), 7.26-7.31 (m, 1 H), 7.21-7.25 5 (m, 1 H), 3.78-3.87 (m, 1 H), 3.49 (s, 2H), 2.15 (s, 3H), 1.91-2.01 (m, 1 H), 1.53-1.65 (m, 4H), 1.41 -1.51 (m, 2H), 1.14-1.26 (m, 2H) HPLC-MS: M/Z = 439, Rt = 2,23 min. Example 228 10 {2-[3-Cyclopentylmethyl-3-(2-fluoro-3-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl} acetic acid CHO N N S O H The title compound was prepared via {2-[3-(2-fluoro-3-methyl-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the 15 synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-fluoro-3-methyl-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 1H NMR (400 MHz, DMSO-d) 6 ppm 7.37 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (t, 1H), 7.10-7.17 (m, 1H), 3.62 (d, 2H), 3.49 (s, 2H), 2.26 (d, 3H), 1.88-1.98 (m, 1H), 1.51-1.63 (m, 4H), 1.40 20 1.49 (m, 2H), 1.13-1.24 (m, 2H) HPLC-MS: M/Z = 424, Rt = 2,12 min. Example 229 {2-[3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido] 25 thiazol-5-ylsulfanyl}- acetic acid WO 2007/006814 PCT/EP2006/064289 198 F F 0 N N N S HK O OH CH3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(3,4-difluoro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 'H NMR (400 MHz, CDC1 3 ) 7.32 (s, 1H), 7.20-6.94 (m, 3H), 4.18-3.81 (m, 1H), 3.52-3.41 (m, 2H), 3.39 (s, 2H), 2.93-2.78 (m, 2H), 1.87-1.68 (m, 4H), 1.60-1.43 (m, 2H), 1.42-1.10 (m, 3H), 0.92 (d, 3H) HPLC-MS: m/z = 470 10 Example 230 (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(3,4,5-trifluoro-phenyl)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid F F FN NNK S bH O IOH HOH Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl 15 cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(3,4,5-trifluoro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 'H NMR (400 MHz, CDC1 3 ) 7.30 (s, 1H), 7.03-6.85 (m, 2H), 4.14-3.77 (m, 1H), 3.51-3.40 (m, 2H), 3.38 (s, 2H), 2.91-2.78 (m, 2H), 1.87-1.70 (m, 4H), 1.60-1.43 (m, 2H), 1.42-1.10 (m, 3H), 0.92 (d, 3H) 20 HPLC-MS: m/z = 488 Example 231 (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,4,5-trifluoro-phenyl)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid WO 2007/006814 PCT/EP2006/064289 199 F F F O N3 N N-KS S H S O OH CH, Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2,4,5-trifluoro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. 5 HPLC-MS: m/z = 488 Example 232 (2-{3-(4-trans-Methyl-cyclohexyl)-3-[2-(2,3,4-trifluoro-phenyl)-ethyl] ureido}-thiazol-5-ylsulfanyl)-acetic acid F F 0 N F IN N-/ S H) O OH 10 CH3 Prepared as described for the synthesis of {2-[3-(2-benzyloxy-ethyl)-3-(4-trans-methyl cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-(2,3,4-trifluoro-phenyl)-ethanol, 4 trans-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. HPLC-MS: m/z = 488 15 Example 233 2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl) ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid oC3 OH bH

CH

3 20 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-chloro- WO 2007/006814 PCT/EP2006/064289 200 benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester 'H NMR (400 MHz, DMSO-d 6 ) 7.53-7.49 (m, 1 H), 7.45-7.41 (m, 1 H), 7.38 (s, 1 H), 7.35-7.27 (m, 2H), 4.62 (s, 2H), 3.99-3.87 (m, 1 H), 3.65-3.57 (m, 2H), 3.56-3.49 (m, 2H), 1.73-1.63 (m, 5 2H), 1.63-1.48 (m, 4H), 1.39 (s, 6H), 1.36-1.22 (m, 1H), 1.11-0.95 (m, 2H), 0.86 (d, 3H) HPLC-MS: m/z = 526 Example 234 2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 10 ylsulfanyl}-2-methyl-propionic acid F 0N N' HCH OH 6bH

CH

3 Prepared as described for the synthesis of {2-[3-[2-(4-fluoro-2-trifluoromethyl-benzyloxy) ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyll-acetic acid using 2-fluoro benzylbromide, (2-hydroxy-ethyl)-(4-trans-methyl-cyclohexyl)-carbamic acid tert-butyl ester 15 and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester 'H NMR (400 MHz, DMSO-d 6 ) 7.48-7.42 (m, 1H), 7.38 (s, 1H), 7.38-7.31 (m, 1H), 7.21-7.13 (m, 2H), 4.58 (s, 2H), 3.98-3.86 (m, 1 H), 3.60-3.54 (m, 2H), 3.52-3.45 (m, 2H), 1.71-1.62 (m, 2H), 1.61-1.45 (m, 4H), 1.39 (s, 6H), 1.36-1.23 (m, 1H), 1.10-0.95 (m, 2H), 0.86 (d, 3H) HPLC-MS: m/z = 510 20 Example 235 {2-[3-(2-Chloro-3-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid F C1 0 N N S OH H 25 The title compound was prepared via {2-[3-(2-chloro-3-fluoro-phenyl)-3-cyclopentylmethyl ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic WO 2007/006814 PCT/EP2006/064289 201 acid, using cyclopentylmethyl-(2-chloro-3-fluoro-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 8 ppm 7.67 (dd, 1 H), 7.46 (dd, 1 H), 7.41 (d, 1 H), 7.37 (s, 1 H), 3.63 (d, 2H), 3.50 (s, 2H), 1.87-1.97 (m, 1 H), 1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.11-1.21 5 (m, 2H) HPLC-MS: M/Z = 425, Rt = 1.82 min. Example 236 {2-[3-(3-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid Br 0 N N S OH 10 H The title compound was prepared via {2-[3-(3-bromo-phenyl)-3-cyclopentylmethyl-ureido] thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-bromo-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic 15 acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 8 ppm 7.55 (t, 1 H), 7.50 (d, 1 H), 7.30-7.39 (m, 3H), 3.71 (d, 2H), 3.50 (s, 2H), 1.88-1.97 (m, 1H), 1.52-1.63 (m, 4H), 1.40-1.49 (m, 2H), 1.12-1.20 (m, 2H) HPLC-MS: M/Z = 470, Rt = 2.19 min. 20 Example 237 {2-[3-(4-Bromo-2-fluoro-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyll acetic acid Br F N H The title compound was prepared via {2-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentylmethyl 25 ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-bromo-2-fluoro-phenyl)-amine and (2-amino-thiazol-5 ylsulfanyl) acetic acid ethyl ester WO 2007/006814 PCT/EP2006/064289 202 1 H NMR (400 MHz, DMSO-d) 8 ppm 7.67 (dd, 1 H), 7.46 (dd, 1 H), 7.41 (d, 1 H), 7.37 (s, 1 H), 3.63 (d, 2H), 3.50 (s, 2H), 1.87-1.97 (m, 1 H), 1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.11-1.21 (m, 2H) HPLC-MS: M/Z = 488, Rt = 2.25 min. 5 Example 238 {2-[3-(2-Bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid YBr O 0 NS OH H The title compound was prepared via {2-[3-(2-bromo-phenyl)-3-cyclopentylmethyl-ureido] 10 thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-bromo-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 8 ppm 7.71-7.76 (m, 1 H), 7.40-7.48 (m, 2H), 7.28-7.39 (m, 15 2H), 3.83-3.99 (m, 1 H), 3.50 (s, 2H), 3.21-3.32 (m, 1 H), 1.93-2.04 (m, 1 H), 1.52-1.71 (m, 4H), 1.41 -1.51 (m, 2H), 1.11-1.28 (m, 2H) HPLC-MS: M/Z = 470, Rt = 2.18 min. Example 239 20 {2-[3-Cyclopentylmethyl-3-(3-methoxy-5-trifluoromethyl-phenyl)-ureido]-thiazol-5 ylsulfanyl}-acetic acid CH3 F OH F H The title compound was prepared via {2-[3-(3-methoxy-5-trifluoromethyl-phenyl)-3 cyclopentylmethyl-u reido]-th iazol-5-ylsu lfanyl}-acetic acid ethyl esterin a similar manner as 25 described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido] th iazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-methoxy-5-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester WO 2007/006814 PCT/EP2006/064289 203 1 H NMR (400 MHz, DMSO-d) 8 ppm 7.38 (s, 1 H), 7.23 (br. s., 1 H), 7.19 (br. s., 2H), 3.85 (s, 3H), 3.74 (d, 2H), 3.50 (s, 2H), 1.89-1.99 (m, 1 H), 1.51-1.64 (m, 4H), 1.40-1.50 (m, 2H), 1.12-1.23 (m, 2H) HPLC-MS: M/Z = 490, Rt = 2.39 min. 5 Example 240 {2-[3-(3-Acetyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid

H

3 C 0 0 s ~OH N N S OH H The title compound was prepared via {2-[3-(3-acetyl-phenyl)-3-cyclopentylmethyl-ureido] 10 thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-acetyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) 6 ppm 7.86-7.92 (m, 1 H), 7.84 (s, 1 H), 7.54-7.60 (m, 15 2H), 7.37 (s, 1 H), 3.75 (d, 2H), 3.50 (s, 2H), 2.60 (s, 3H), 1.88-2.00 (m, 1 H), 1.51 1.64 (m, 4H), 1.38-1.50 (m, 2H), 1.12-1.24 (m, 2H) HPLC-MS: M/Z = 434, Rt = 2.08 min. 20 Example 241 {2-[3-(1-Acetyl-2,3-dihydro-1 H-indol-6-yI)-3-cyclopentylmethyl-ureido]-thiazol-5 ylsulfanyl}-acetic acid H 3 C N N S OH & H The title compound was prepared via {2-[3-(1 -acetyl-2,3-dihydro-1 H-indol-6-yl)-3 25 cyclopentylmethyl-ureido]-thiazo-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]- WO 2007/006814 PCT/EP2006/064289 204 thiazol-4-yl}-acetic acid, using 1-[6-(cyclopentylmethyl-amino)-2,3-dihydro-indol-1 -yl] ethanone and (2-amino-thiazol-5-ylsulfanyl) acetic acid ethyl ester 1 H NMR (400 MHz, DMSO-d) ppm 7.92 (d, 1 H), 7.35 (s, 1 H), 7.26 (d, 1 H), 6.92 (dd, 1 H), 4.14 (t, 2H), 3.63 (d, 2H), 3.49 (s, 2H), 3.16 (t, 2H), 2.16 (s, 3 H), 1.90-2.01 (m, 1H), 1.51 5 1.65 (m, 4 H), 1.39-1.50 (m, 2H), 1.14-1.24 (m, 2H). HPLC-MS: M/Z = 475, Rt = 1.82 min. Example 242 10 FURTHER COMPOUNDS ACCORDING TO THE INVENTION A non-limiting example of further compounds according to the invention are listed in Table 1. The preparation of the compounds Aa - Bx of general formula (1) of the present invention may be performed according to one or more of the described methods I-K as indicated for 15 each compound in Table 1. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the re actions can be successfully performed by conventional modifications known to those skilled in the art, which is, by appropriate protection of interfering groups, by changing to other con 20 ventional reagents, or by routine modification of reaction conditions. Alternatively, other reac tions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may be prepared by a person skilled in the art in analogy with the preparation of similar known compounds or by the General procedures A through K described herein. 25 Table 1 Com- Structure Name Method pound 0 {2-[3-(2-Benzyloxy-ethyl)-3-(4- (1) Og AN d OOH methyl-cyclohexyl)-ureido] Aa thiazole-5-sulfonyl}-acetic acid WO 2007/006814 PCT/EP2006/064289 205 0 0O {2-[3-[2-(2-Methyl-benzyloxy)- (1) O N ," 5 OH ethyl]-3-(4-methyl-cyclohexyl) Ab H ureido]-thiazole-5-sulfonyll acetic acid F O 1 {2-[3-[2-(2-Fluoro-benzyloxy)- (1) O N S OH ethyl]-3-(4-methyl-cyclohexyl) Ac H ureido]-thiazole-5-sulfonyll acetic acid cI 0 O {2-[3-[2-(2-Chloro-benzyloxy)- (1) N N'S 0" OH ethyl]-3-(4-methyl-cyclohexyl) H ureido]-thiazole-5-sulfonyll Ad acetic acid F F 0 (2-{3-(4-Methyl-cyclohexyl)-3- (1) F N N ",9O [2-(2-trifluoromethyl Ae H benzyloxy)-ethyl]-ureido} thiazole-5-sulfonyl)-acetic acid F F 0 {2-[3-[2-(4-Fluoro-2- () F F N0 N dSOH trifluoromethyl-benzyloxy) H ethyl]-3-(4-methyl-cyclohexyl) Af ureido]-thiazole-5-sulfonyll acetic acid F CI O {2-[3-[2-(2-Chloro-4-fluoro- (I) O~ N S OH benzyloxy)-ethyl]-3-(4-methyl H cyclohexyl)-ureido]-thiazole-5 Ag bH sulfonyll-acetic acid F F N {2-[3-[2-(2,4-Difluoro- (I) O N S OH benzyloxy)-ethyl]-3-(4-methyl Ah cyclohexyl)-ureido]-thiazole-5 sulfonyll-acetic acid WO 2007/006814 PCT/EP2006/064289 206 0 2-{2-[3-(2-Benzyloxy-ethyl)-3- (1) O N N , O OH (4-methyl-cyclohexyl)-ureido] N N S 0 H thiazole-5-sulfonyl}-2-methyl Ai propionic acid o 2-Methyl-2-{2-[3-[2-(2-methyl- (1) O Nll 0 OH benzyloxy)-ethyl]-3-(4-methyl H cyclohexyl)-ureido]-thiazole-5 Aj sulfonyl}-propionic acid F lo 2-{2-[3-[2-(2-Fluoro- (1) O 'NS N O OH benzyloxy)-ethyl]-3-(4-methyl H cyclohexyl)-ureido]-thiazole-5 Ak sulfonyl}-2-methyl-propionic acid c0 N o 2-{2-[3-[2-(2-Chloro- (1) o N A O OH benzyloxy)-ethyl]-3-(4-methyl N H cyclohexyl)-ureido]-thiazole-5 Al sulfonyl}-2-methyl-propionic acid F F 2-Methyl-2-(2-{3-(4-methyl- (1) F N N cyclohexyl)-3-[2-(2 H trifluoromethyl-benzyloxy) Am ethyl]-ureido}-thiazole-5 sulfonyl)-propionic acid F F 2-{2-[3-[2-(4-Fluoro-2- (1) F 0 N F OH trifluoromethyl-benzyloxy) H ethyl]-3-(4-methyl-cyclohexyl) An ureido]-thiazole-5-sulfonyl}-2 methyl-propionic acid WO 2007/006814 PCT/EP2006/064289 207 F F o 2-{2-[3-[2-(2,4-Difluoro- (1) O O OH benzyloxy)-ethyl]-3-(4-methyl N S 0 H cyclohexyl)-ureido]-thiazole-5 Ao sulfonyl}-2-methyl-propionic acid O {2-[3-(4-Methyl-cyclohexyl)-3- (1) N N 0 OH (3-phenoxy-propyl)-ureido] H thiazole-5-sulfonyl}-acetic acid Ap io 2-Methyl-2-{2-[3-(4-methyl- (1) N A 'O OH cyclohexyl)-3-(3-phenoxy H propyl)-ureido]-thiazole-5 Aq sulfonyl}-propionic acid 0 N00 {2-[3-(4-Methyl-cyclohexyl)-3- (1) N N O , 0 OH phenethyl-ureido]-thiazole-5 H sulfonyll-acetic acid Ar {2-[3-[2-(4-Methoxy-phenyl)- (1) N N , OH ethyl]-3-(4-methyl-cyclohexyl) N N 0 ureido]-thiazole-5-sulfonyl} As acetic acid F {2-[3-[2-(3-Fluoro-4-methoxy- (1) 0 N , O phenyl)-ethyl]-3-(4-methyl -o OH N N S 0 cyclohexyl)-ureido]-thiazole-5 At sulfonyll-acetic acid WO 2007/006814 PCT/EP2006/064289 208 {2-[3-[2-(4-Ethoxy-phenyl)- (1) O N \ ethyl]-3-(4-methyl-cyclohexyl) N N S O OH ureido]-thiazole-5-sulfonyl} Au acetic acid O 2-Methyl-2-{2-[3-(4-methyl- (1) O N O OH cyclohexyl)-3-phenethyl H O u reido]-th iazole-5-su Ifonyll Av propionic acid N A2-{2-[3-[2-(4-Methoxy-phenyl)- (1) N NOethyl]-3-(4-methyl-cyclohexyl) "SoOH N S O ureido]-thiazole-5-sulfonyl}-2 H Aw methyl-propionic acid I F 2-{2-[3-[2-(3-Fluoro-4- (1) O methoxy-phenyl)-ethyl]-3-(4 ~ OH N N O methyl-cyclohexyl)-ureido] Ax thiazole-5-sulfonyl}-2-methyl propionic acid 2-{2-[3-[2-(3-Fluoro-4- (1) O 0 N methoxy-phenyl)-ethyl]-3-(4 sN N ilOO OH methyl-cyclohexyl)-ureido] Ay H thiazole-5-sulfonyl}-2-methyl propionic acid 0 3-{2-[3-(2-Benzyloxy-ethyl)-3- (J) S4 OH(4-methyl-cyclohexyl)-ureido] thiazol-5-ylsulfanyl}-2,2 Az dimethyl-propionic acid WO 2007/006814 PCT/EP2006/064289 209 O 3-{2-[3-[2-(2-Fluoro- (J) F 0 4 OHbenzyloxy)-ethyl]-3-(4-methyl BHH cyclohexyl)-ureido]-thiazol-5 Ba ylsulfanyl}-2,2-dimethyl propionic acid 0O 2,2-Dimethy-3-{2-[3-[2-(2- (J) O Smethyl-benzyloxy)-ethyl]-3-(4 N Smethyl-cyclohexyl)-ureido] Bb thiazol-5-ylsulfanyll-propionic acid O 3-{2-[3-[2-(2-Chloro- (J) N - OH benzyloxy)-ethyl]-3-(4-methyl N S H cyclohexyl)-u reido]-th iazol-5 Bc ylsu If anyl}-2 ,2-dimethyl propionic acid F F OH 2,2-Dimethyl-3-(2-{3-(4- (J) F N methyl-cyclohexyl)-3-[2-(2 H trifluoromethyl-benzyloxy) Bd ethyl]-u reido}-th iazol-5 ylsulfanyl)-propionic acid OH 2,2-Dimethyl-3-{2-[3-(4-methyl- (J) S Ocyclohexyl)-3-(3-phenoxy O N S H propyl)-ureido]-thiazol-5 Be ylsulfanyl}-propionic acid 3-{2-[3-[3-(2-Chloro-phenoxy)- (J) CI OH S Hpropyl]-3-(4-methyl O--- N S H cyclohexyl)-ureido]-thiazol-5 Bf ylsulfanyl}-2,2-dimethyl propionic acid WO 2007/006814 PCT/EP2006/064289 210 ci O 3-{2-[3-[3-(3-Chloro-phenoxy)- (J) OH O N 4 Opropyl]-3-(4-methyl H cyclohexyl)-u reido]-th iazol-5 Bg ylsu If anyl}-2,2-dimethyl propionic acid 0 3-{2-[3-[3-(4-Chloro-phenoxy)- (J) I O SNH propyl]-3-(4-methyl Bh H cyclohexyl)-u reido]-th iazol-5 ylsu If anyl}-2,2-dimethyl propionic acid O 2,2-Dimethyl-3-{2-[3-(4-methyl- (J) OH 0OH cyclohexyl)-3-phenethyl s ureido]-thiazol-5-ylsulfanyl} Bi propionic acid 0 3-{2-[3-[2-(4-Methoxy-pheny)- (J) NS OH ethyl]-3-(4-methyl-cyclohexyl) NN ureido]-thiazol-5-ylsulfanyl} Bj 2,2-dimethyl-propionic acid O 3-{2-[3-[2-(4-Ethoxy-phenyl)- (J) S OH ethyl]-3-(4-methyl-cyclohexyl) N S ureido]-thiazol-5-ylsulfanyl} Bk 2,2-dimethyl-propionic acid F O 3-{2-[3-[2-(3-Fluoro-4- (J) NS OH methoxy-phenyl)-ethyl]-3-(4 H methyl-cyclohexyl)-ureido] BI th iazol-5-ylsu If anyl}-2,2 dimethyl-propionic acid WO 2007/006814 PCT/EP2006/064289 211 S0{2-[3-(2-Benzylsulfanyl-ethy)- (K) S N N S OH 3-(4-methyl-cyclohexyl) H ureido]-thiazol-5-ylsulfanyll Bm acetic acid ,0N _/Lo 2-{2-[3-(2-Benzylsulfanyl- (K) S N N )L s OH ethyl)-3-(4-methyl-cyclohexyl) H u reido]-th iazol-5-ylsu Ifanyl}-2 Bn methyl-propionic acid IU / {2-[3-(2-Benzylsulfanyl-ethyl)- (K) + (1) S N N S OH 3-(4-methyl-cyclohexyl) -H ureido]-thiazole-5-sulfonyll Bo acetic acid O 2-{2-[3-(2-Benzylsulfanyl- (K) + (1) S N N . OH ethyl)-3-(4-methyl-cyclohexyl) N N s 0O H u reido]-th iazole-5-su Ifonyl}-2 Bp methyl-propionic acid 0O 3-{2-[3-(2-Benzylsulfanyl- (K) + (J) SNO ethyl)-3-(4-methyl-cyclohexyl) Bq H ureido]-thiazol-5-ylsulfanyll 2,2-dimethyl-propionic acid 0O 3-{2-[3-(2-Benzylsulfanyl- (K) + (1) N OH ethyl)-3-(4-methyl-cyclohexyl) Br H ureido]-thiazole-5-sulfonyl}-2,2 dimethyl-propionic acid WO 2007/006814 PCT/EP2006/064289 212 0O 2,2-Dimethyl-3-{2-[3-(4-methyl- (K) + (J) S0S s cyclohexyl)-3-(3 Bs phenylsulfanyl-propyl)-ureido] Bs thiazol-5-ylsulfanyll-propionic acid 0O 2,2-Dimethyl-3-{2-[3-(4-methyl- (K) + (1) O N cyclohexyl)-3-(3- + (J) S ' N 'kN S " O - H O phenylsulfanyl-propyl)-ureido] Bt th iazole-5-su Ifonyl}-propionic acid 0 N O / {2-[3-(4-Methyl-cyclohexyl)-3- (K) S NN J S OH (3-phenylsulfanyl-propyl) H ureido]-thiazol-5-ylsulfanyll Bu acetic acid io 2-Methyl-2-{2-[3-(4-methyl- (K) N S OH cyclohexyl)-3-(3 H phenylsulfanyl-propyl)-uredo] Bv thiazol-5-ylsulfanyll-propionic acid ON O {2-[3-(4-Methyl-cyclohexyl)-3- (K) + (1) a S N N O I OH (3-phenylsulfanyl-propyl) ureido]-thiazole-5-sulfonyll Bw acetic acid o 2-Methyl-2-{2-[3-(4-methyl- (K) + (1) S sL N O OH cyclohexyl)-3-(3 phenylsulfanyl-propyl)-ureido] Bx thiazole-5-sulfonyll-propionic acid

Claims (16)

1. A compound having the formula: R3 0 N ' NA H 5 R30 wherein R 3 is selected from the group consisting of phenoxy and benzyloxy, each of which is optionally substituted with one or more substituents independently selected from R 12 10 R 12 is F, Cl, Br, -CF 3 , -CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH 3 , or -S(O) 2 -CH 3 ; R 3 0 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy, or cyclopropyl-methoxy, each of which is optionally substituted with one or more 15 substituents independently selected from R"; 8 S A is R 8 is methylthio, isopropylthio, ethylthio, or 2-methylpropylthio, each of which is 20 substituted with one or more substituents independently selected from R 3 4 ; R 34 is carboxy; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R 12 is F, Cl, Br, methyl, or ethyl. 25

3. The compound of claim 1, wherein R 3 0 is methyl or ethyl. - 214

4. The compound of claim 1, wherein the compound is selected from the group consisting of: 2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2-methyl-propionic acid; 5 or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein the compound is 2-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2-methyl-propionic acid. 10

6. The compound of claim 1, wherein the compound is selected from the group consisting of: 2-{2-[3-[2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2-methyl-propionic acid; 15 or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein the compound is 2-{2-[3-(2-(2-Fluoro-benzyloxy)-ethyl]-3-(4-trans-methyl-cyclohexyl)-ureido]-thiazol-5 ylsulfanyl}-2-methyl-propionic acid. 20

8. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 25

9. The composition of claim 8, wherein the composition is in a unit dosage form comprising from about 0.05 mg to about 1000 mg of a compound according to any one of claims 1 to 7.

10. The composition of claim 9, wherein the unit dosage form comprises from about 30 0.1 mg to about 500 mg of a compound according to any one of claims 1 to 7.

11. The composition of claim 9 or claim 10, wherein the unit dosage form comprises from about 0.5 mg to about 200 mg of a compound according to any one of claims 1 to 7. -215

12. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of a metabolic disorder, for blood glucose lowering, for the treatment of hyperglycemia, for the treatment of IGT, for the treatment of Syndrome X, for the treatment of impaired fasting glucose (IFG), for the treatment of type-2 5 diabetes, for the treatment of type-1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type-2 diabetes, for delaying the progression of non-insulin requiring type-2 diabetes to insulin requiring type-2 diabetes, for the treatment of dys lipidemia, for the treatment of hyperlipidemia, for the treatment of hypertension, for lowering of food intake, for appetite regulation, for the treatment of obesity, for 10 regulating feeding behaviour, or for enhancing the secretion of enteroincretins.

13. Use according to claim 12, for the treatment of an indication selected from the group consisting of hyperglycemia, IGT, insulin resistance syndrome, syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hypertension, and obesity. 15

14. A method for treating a metabolic disorder, for lowering blood glucose levels, treating hyperglycemia, treating IGT, treating Syndrome X, treating impaired fasting glucose (IFG), treating type-2 diabetes, treating type-1 diabetes, delaying the progression of impaired glucose tolerance (IGT) to type-2 diabetes, delaying the progression of non-insulin requiring type-2 diabetes to insulin requiring type-2 diabetes, 20 treating dyslipidemia, treating hyperlipidemia, treating hypertension, lowering of food intake, appetite regulation, treating obesity, regulating feeding behaviour, or enhancing the secretion of enteroincretins said method comprising the step of administering to a subject in need thereof a compound according to any one of claims 1 to 7.

15. A method of treating an indication selected from the group consisting of 25 hyperglycemia, IGT, insulin resistance syndrome, syndrome X, type-2 diabetes, type-1 diabetes, dyslipidemia, hypertension, and obesity said method comprising the step of administering to a subject in need thereof a compound according to any one of claims 1 to 7. 30

16. A compound according to claim 1; use of a compound according to claim 12 or claim 13; or a method of treatment according to claim 14 or claim 15, substantially as herein described with reference to any one or more of the examples but excluding comparative examples.